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  1. The NY Times has a general-interest-level article on the crucial role the cell nucleolus plays in aging: https://www.nytimes.com/2018/05/20/science/nucleolus-cells-aging.html?rref=collection%2Fsectioncollection%2Fscience The technical article is here: https://www.cell.com/trends/cell-biology/fulltext/S0962-8924(18)30063-1 - Richard Schulman Editor, https://foundersbroadsheet.com
  2. Sthira

    Senolytic Sensational

    Anyone jumping up and down yet? http://www.ebiomedicine.com/article/S2352-3964(17)30116-0/fulltext "Cell senescence is increasingly recognized as a major contributor to the loss of health and fitness associated with aging. Senescent cells accumulate dysfunctional mitochondria; oxidative phosphorylation efficiency is decreased and reactive oxygen species production is increased. In this review we will discuss how the turnover of mitochondria (a term referred to as mitophagy) is perturbed in senescence contributing to mitochondrial accumulation and Senescence-Associated Mitochondrial Dysfunction (SAMD). We will further explore the subsequent cellular consequences; in particular SAMD appears to be necessary for at least part of the specific Senescence-Associated Secretory Phenotype (SASP) and may be responsible for tissue-level metabolic dysfunction that is associated with aging and obesity. Understanding the complex interplay between these major senescence-associated phenotypes will help to select and improve interventions that prolong healthy life in humans."
  3. Hello, I have a medical background and created an app to help you understand which of 10 habits could reduce your mortality risk (based on scientific research) and develop them using gamification. I'm looking for testers, so let me know if this could be useful to you. Thanks.
  4. http://www.rochester.edu/newscenter/study-identifies-key-factor-in-dna-damage-associated-with-aging-222862/
  5. All, There is a new paper out [1] (popular account) that seems to me to do a pretty good job summarizing what we know about the different causes of aging. They have the same perspective as Aubrey, Michael & SENS - namely that at its root aging is a result of metabolic damage accumulation. But they appear to have a slightly different taxonomy than Aubrey's "7 deadly causes", although I'll leave it to Michael to map between the two. Here is there graphic showing the "Hallmarks of Aging": One thing that jumped out at me (and that I've highlighted above in yellow) was the role peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC1α) appears to play in the various hallmarks of aging. In fact, a drop in PGC1α signalling is implicated in four of the nine hallmarks of aging. This interests me, because PGC1α promotes mitochondria biogenesis, and is upregulated by cold exposure [2], as we've seen many times on the cold exposure thread. Sadly, the authors don't mention cold exposure as a potential means to ameliorate the aging process. Instead they focus on CR, amino-acid restriction, CR-mimetics, time-restricted feeding, and exercise as the most promising longevity interventions. Oh well, someday the benefits of cold exposure will be more widely recognized. Overall it's an fascinating paper covering both the mechanisms of aging and (some of) the best ideas we have for what can be done about it today. --Dean ---------- [1] Cell 166, August 11, 2016 Metabolic Control of Longevity Carlos Lo´ pez-Otı´n,1,* Lorenzo Galluzzi,2,3,4,5,6,7 Jose´ M.P. Freije,1 Frank Madeo,8,9 and Guido Kroemer Free full text: http://www.cell.com/cell/pdf/S0092-8674(16)30981-3.pdf Several metabolic alterations accumulate over time along with a reduction in biological fitness, suggesting the existence of a ‘‘metabolic clock’’ that controls aging. Multiple inborn defects in metabolic circuitries accelerate aging, whereas genetic loci linked to exceptional longevity influence metabolism. Each of the nine hallmarks of aging is connected to undesirable metabolic alterations. The main features of the ‘‘westernized’’ lifestyle, including hypercaloric nutrition and sedentariness, can accelerate aging as they have detrimental metabolic consequences. Conversely, lifespan-extending maneuvers including caloric restriction impose beneficial pleiotropic effects on metabolism. The introduction of strategies that promote metabolic fitness may extend healthspan in humans. PMID: Not available DOI: http://dx.doi.org/10.1016/j.cell.2016.07.031 ------------ [2] Adv Physiol Educ. 2006 Dec;30(4):145-51. PGC-1alpha: a key regulator of energy metabolism. Liang H(1), Ward WF. Author information: (1)Department of Cellular and Structural Biology, Audie Murphy Veterans Administration Medical Center and University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis. PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of muscle tissue to a fiber-type composition that is metabolically more oxidative and less glycolytic in nature, and it participates in the regulation of both carbohydrate and lipid metabolism. It is highly likely that PGC-1alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes. DOI: 10.1152/advan.00052.2006 PMID: 17108241
  6. Dean Pomerleau

    Metabolism, Aging, CR & Exercise

    I found this new paper %5B1%5D posted by Al Pater to the now defunct (RIP) CR mailing list to be a very interesting model of aging and how it relates to metabolism. I was particularly interested in how the authors explained the benefit (or at least, the non-harm) of exercise when it comes to lifespan, despite the fact that a naive interpretation, based on the Rate-of-Living Theory, would suggest that exercise requires more calories which will inevitably result in greater metabolic damage (e.g. via reactive oxygen species (ROS) generation), and thus faster aging. They offer a theory which compartmentalizes metabolism into several components, illustrated schematically in Fig 4: The black (outside) box represents the total metabolism of an organism, either being fed ad lib (left bar) vs. CR (middle bar). In order for the organism to grow (i.e. deposition of new biomass), it must not only sequester matter into new tissue which stores energy and therefore requires ingested calories (green box), but also active expenditure of energy to convert the food into living (muscle, fat or bone) tissue, which they call biosynthesis (blue box). With dietary restriction, the total metabolic budget is lower (middle bar shorter than left bar). With fewer calories to go around, the body decides to create less new tissue, cutting down on the green box to stay "within budget". With less tissue to create, the active cost of biosynthesis that would be required to create that tissue is also reduced (blue box) in the CR condition. That leaves more net energy available for "protection (scavaging and repair)" (yellow box) in the CR condition than in the AL condition, leading to better health maintenance and increased longevity. In the bulk of the paper, the authors develop equations to quantify these relationships, explain known (sometimes paradoxical) observations about the relationship between metabolism and longevity, and to make predictions. What it seems to boil down to is that if an organism stays small (relative to the 'normal' size for its species), it will tend to live longer. They show an interesting graph (Fig 5) to support this hypothesis, which illustrates how lifespan extension appears linearly related to the degree of body mass reduction induced by either CR or genetic manipulation of growth hormone: What I found most interesting personally was their discussion of the impact of exercise on metabolism and lifespan. Here is a quote from that section of the paper: [T]he model can be generalized to include the variation in activity level. As shown in Fig. 4, with a limited food supply, an increase in activity would further suppress growth. Thus, depending on the degree of the increase in activity, the adult mass of DR animals (MDR) will be even smaller. In Eq. (3), lifespan extension is proportional to the body mass reduction (M/MDR − 1). So, if MDR is smaller due to the increase in activity, the lifespan extension will be larger. There is no empirical data to test this prediction directly and quantitatively, because most studies did not measure the energy cost of the increased activity level. But the results from Holloszy (1997) [2] support this prediction indirectly by showing that the major determinant of lifespan extension is the body mass reduction even if activity level varies [my emphasis]. Holloszy (1997) reported the lifespan, food consumption, and body mass of four groups of male Long-Evans rats reared at different levels of food supply and exercises: ad libitum (AL)-runner, AL-sedentary, DR-runner, and DR-sedentary. The peak body mass (M and MDR) of these four groups rank in such an order: AL-sedentary (597 g) > AL-runner (420 g) > DR-runner (333 g) = DR-sedentary (330 g). Equation (3) predicts that their lifespan will be in the opposite order. The data supports this prediction: AL-sedentary (858 days) < AL-runner (973 days) < DR-runner (1058 days) = DR-sedentary (1051 days). Note, in this study, although they are both under DR, DR-runners consumed more food (13.4 g/day) than DR-sedentary group (10 g/day). So the runner and sedentary groups ended up with the same body mass (∼330 g). The interesting result is that despite the different exercise and food levels, the same body mass led to the same lifespan (∼1050 days) in these two groups, exactly as our model predicts [my emphasis]. We postulate that if DR-runner and DR-sedentary were fed with the same level of food, then the runners will be have a smaller body mass, and therefore a longer lifespan. So the calorie-restricted running rats ate 34% more calories than the sedentary calorie-restricted rats, but as a result of their extra energy expenditure, weighed the same, and lived just as long as the sedentary CR rats. The authors point out that while burning more calories will usually generate more damaging free radicals, when calories are burned in exercise they are burned "more cleanly", and hence don't generate as many ROS's as when burned under sedentary conditions. To quote the paper again: The percentage of electron leak can also vary during exercises, where the mitochondrial respiration transits from state 4 to state 3 (Barja, 2007 and Barja, 2013). Under state 4 (resting respiration), oxygen consumption is low, proton-motive force is high, and ROS production is high (Barja, 2013 and Harper et al., 2004), whereas under state 3 (active respiration), ROS production reduces rapidly (Boveris and Chance, 1973, Boveris et al., 1972 and Loschen et al., 1971). So if exercise trains mitochondria to operate in state 3 both during exercise and (possibly) during rest as well, the net effect of exercise on free radical production may not be very significant. And if exercise also induces a hormetic effect that increases free radical scavenging (which there is quite a bit of evidence to support), the net result could be less damage from free radicals despite more calories burned as a result of exercise. This seems to contradict the oft-cited mantra among some human CR practitioners of "calories, calories, calories" - i.e. its reducing calories that matters, whether or not it leads to weight loss, and attaining a low weight as a result of extra activity/exercise won't be equivalently beneficial for longevity as a higher degree of (semi-sedentary) CR. Given that Holloszy's paper [2] is from 1997, I'm sure we hashed all this out on the old CR mailing list many years ago, and perhaps MR will point to that old thread :). But I thought it was interesting (and encouraging) given my recent disclosure that lately I've been eating more calories but exercising a lot more to maintain a very CR-like weight (BMI ~17.5). --Dean ----------------------------------------------------- [1] On the complex relationship between energy expenditure and longevity: Reconciling the contradictory empirical results with a simple theoretical model. Hou C, Amunugama K.[/size] Mech Ageing Dev. 2015 Jun 15;149:50-64. doi: 10.1016/j.mad.2015.06.003. [Epub ahead of print] PMID:26086438 http://www.sciencedirect.com/science/article/pii/S0047637415000846 http://ac.els-cdn.com/S0047637415000846/1-s2.0-S0047637415000846-main.pdf?_tid=e680437e-1d32-11e5-8323-00000aacb361&acdnat=1435454195_8ec497f0141d9e67cb89cf2909758cd4 Abstract The relationship between energy expenditure and longevity has been a central theme in aging studies. Empirical studies have yielded controversial results, which cannot be reconciled by existing theories. In this paper, we present a simple theoretical model based on first principles of energy conservation and allometric scaling laws. The model takes into considerations the energy tradeoffs between life history traits and the efficiency of the energy utilization, and offers quantitative and qualitative explanations for a set of seemingly contradictory empirical results. We show that oxidative metabolism can affect cellular damage and longevity in different ways in animals with different life histories and under different experimental conditions. Qualitative data and the linearity between energy expenditure, cellular damage, and lifespan assumed in previous studies are not sufficient to understand the complexity of the relationships. Our model provides a theoretical framework for quantitative analyses and predictions. The model is supported by a variety of empirical studies, including studies on the cellular damage profile during ontogeny; the intra- and inter-specific correlations between body mass, metabolic rate, and lifespan; and the effects on lifespan of (1) diet restriction and genetic modification of growth hormone, (2) the cold and exercise stresses, and (3) manipulations of antioxidant. -------------------- [2] J.O. Holloszy Mortality rate and longevity of food-restricted exercising male rats: a reevaluation J. Appl. Physiol., 82 (1997), pp. 399–403 Abstract Food restriction increases the maximal longevity of rats. Male rats do not increase their food intake to compensate for the increase in energy expenditure in response to exercise. However, a decrease in the availability of energy for growth and cell proliferation that induces an increase in maximal longevity in sedentary rats only results in an improvement in average survival, with no extension of maximal life span, when caused by exercise. In a previous study (J. O. Holloszy and K. B. Schechtman. J. Appl. Physiol. 70: 1529-1535, 1991), to test the possibility that exercise prevents the extension of life span by food restriction, wheel running and food restriction were combined. The food-restricted runners showed the same increase in maximal life span as food-restricted sedentary rats but had an increased mortality rate during the first one-half of their mortality curve. The purpose of the present study was to determine the pathological cause of this increased early mortality. However, in contrast to our previous results, the food-restricted wheel-running rats in this study showed no increase in early mortality, and their survival curves were virtually identical to those of sedentary animals that were food restricted so as to keep their body weights the same as those of the runners. Thus it is possible that the rats in the previous study had a health problem that had no effect on longevity except when both food restriction and exercise were superimposed on it. Possibly of interest in this regard, the rats in this study did considerably more voluntary running than those in the previous study. It is concluded that 1) moderate caloric restriction combined with exercise does not normally increase the early mortality rate in male rats, 2) exercise does not interfere with the extension of maximal life span by food restriction, and 3) the beneficial effects of food restriction and exercise on survival are not additive or synergistic.
  7. All, Over on the Body-mass index and all-cause mortality thread, TomB posted the following, asking about what we might learn from the lifestyle and biomarkers of the very old in order to optimize our own diets and lifestyles. TomB said (my emphasis): [Note: the blue highlights above will factor into the discussions below] That other Michael (i.e. Mike Lustgarten hereafter referred to as 'Mike' to avoid confusion) and I have had several debates on this subject before on the CR Facebook forum. Namely, Mike likes to look at the characteristics (e.g. BMI, or selenium level) of very long-lived people (i.e. who've made it into their 90s or 100s), declare "they must be doing something right!" and target those same biomarker levels, diet characteristics and/or lifestyle practices for himself, and advocate others do the same to maximize their chance of living a long time. But as I've tried to point out to him on several occasions (relatively unsuccessfully it would seem), this approach to diet and lifestyle optimization is naive and fraught with problems. Here are the reasons why. It all boils down to one overarching observation - we're not like very old people. But just how we are unlike them, and why it matters, will take some unpacking. Freakishly good gene combinations - Perhaps the most common way for people these days to reach a very ripe old age is to have freakishly good genes. This allows them to avoid the major killers, like heart disease and cancer, often despite bad diet and lifestyle habits. Think of this as the George Burns effect. Actor George Burns lived to 100 despite smoking 10-15 cigars per day for 70 years (ref). Don't try that at home sports fans! The same thing is happening when you hear on TV about the latest 110 year old who attributes their longevity to "eating two strips of bacon per day" or "drinking whisky". In short, just because someone with freakishly good genes got away with a bad habit and lived to a ripe old age, doesn't mean you could, or should, try to emulate them, since most of us have crappy, run-of-the-mill gene combos, by definition, which means emulating such behavior would kill us quick. Survivor bias - In addition to a few folks with freakishly good genes, in any large population, there will also be a few folks with average genes who get lucky, and live to a ripe old age, avoiding the major killers. In fact, they might have bad genes or lifestyle habits that would on average shorten lifespan, but because they got lucky, they lived a long time. Here are a couple great examples of survivor bias (and/or other explanations discussed below) from the study Tom posted above (PMID:25446984), and that I've highlighted in blue. Notice above in that study the people who lived a very long time, into their 90s and 100s, had significantly lower levels of calcium and iron than did middle-aged controls. What gives? Isn't calcium supposed to be good for bones and iron important for avoiding anemia-complications and having a healthy immune system? Those benefits of Ca and Fe may hold true for middle-aged folks, and even the average senior. But at the same time, calcium can calcify arteries, and iron can cause oxidative damage, both of which can exacerbate the major killers - heart disease and cancer. So if you are one of those very rare individuals with either good genes and/or very good luck, you can get away with keeping Ca and Fe on the low (deficient) side, and avoid Ca and Fe deficiency-related maladies that would kill off the average person early - like a hip fracture from weak bones or a respiratory infection from a weak immune system. If you get lucky and escape those downsides of low Ca and Fe, then you are golden because keeping them low will help you avoid heart disease and cancer and hence live a long time. But if you're like the average person, low Ca and/or Fe will lead to broken bones and/or infections that will cut your life short on average. In other words, low Ca and/or low Fe will harm most people, and only benefit a lucky few. Another good example here is directly related to immunity - namely white blood cell (WBC) count. Several studies (discussed in http://dx.doi.org/10.1371/journal.pone.0127550) have found that that oldest of the old have low WBC. This is great for them, since it enabled them to avoid the major diseases of aging, which are triggered by inflammation. But they very well may have gotten luck or had good genes, enabling them to avoid infections that would normally have killed an average person with such a low WBC. In short, it doesn't necessarily pay for the average person to try to emulate the blood chemistry profile of the very old. Late Life / Near Death Changes - It's not just good genes or survivor bias (i.e. freakish luck) that sets the oldest of the old apart from the rest of us, and which makes them poor models to emulate. Why? Because biomarkers change drastically later in life, and especially when you are approaching death, which centenarians almost invariably are. So their blood chemistry levels when they are old aren't necessarily reflective of what got them to a ripe old age. Serum cholesterol is a great example of this. For various reasons, ranging from intestinal parasites to cancer, serum cholesterol tends to drop precipitously as people get sick and approach death. This can result in several misleading observations. First, old people with the highest cholesterol often live longer (i.e. have a lower mortality rate) than old people with low cholesterol, due to reverse causality. That is, the folks with low cholesterol are low because they've got a disease that will soon kill them. This observation (i.e. mortality risk is lowest in elderly folks with high cholesterol) is often pointed to by saturated fat apologists who like to claim keeping cholesterol from getting too low is critical for health and that low cholesterol is as bad or worse than high cholesterol. Bogus argument. Conversely, the oldest of the old, e.g. centenarians or supercentenarians, who are almost invariably within a year or two of death, may exhibit freakishly low cholesterol, for the same "reverse causality" reason - i.e. they are close to death causing low cholesterol. In both cases, the cholesterol level these old or freakishly old folks exhibit when they get to their ripe old age tells us nothing about what cholesterol level is best to get you to old age. For that we can look at longitudinal studies, that show low cholesterol in middle age is associated with improved longevity, for obvious reasons. That's why, BTW, studies of the freakishly old often look at their offspring or (younger) siblings as well, to see what characteristics people with similar genes had when they were younger, to avoid these late life changes/biases. In summary, looking at the blood chemistry, diet and/or lifestyle of very old people and trying to emulate them is fraught with difficulty, and therefore ill-advised. This is unfortunate, since it makes us much more reliant on longitudinal studies in people and intervention studies in animals, which have their own pitfalls, as we are all well-aware. --Dean
  8. All, Sthira has several times (e.g. here) plaintively called for the more widespread application of advances in the burgeoning field of artificial intelligence to the problem of defeating aging. You would think Google-owned Calico would be leading the charge in the arena, and perhaps they are. But Calico's inner workings are quite opaque, and judging by the apparent vaporware status of the glucose-monitoring contact lenses supposedly under development at Verily, that other Google-owned, health technology-focused company, we may be waiting a long time for results from Calico... Fortunately, it appears others in the tech industry are picking up the torch of applying AI to the problem of aging. This announcement talks about a partnership between the Life Extension Foundation (LEF) and Insilico Medicine, a Big Data / AI startup that was spun off from Johns Hopkins University that is focused on applying deep learning to drug discovery. According to the press release, the partnership will focus on discovering "effective nutraceuticals that promote the young healthy state in old tissues and support health and longevity." In a bit more detail: Insilico Medicine will focus on applying advanced signaling pathway activation analysis techniques and deep learning algorithms to find nutraceuticals that mimic the tissue-specific transcriptional response of many known interventions and pathways associated with health and longevity. They will also search for dietary ingredients referred to as "geroprotectors" that mimic the young healthy signaling state in older human tissues. Life Extension will use this information to develop novel nutraceutical products to support health and longevity. While I'm not very optimistic about the prospects of dramatic life extension via pharmacological interventions, it's good to see AI, Big Data and deep learning being applied to "advanced signaling pathway activation analysis". It seems to me that any true longevity breakthrough will require this sort of analysis to help unravel the incredible complexity of human metabolism as it relates to aging, whether it can ultimately be translated into "geroprotector" nutraceuticals or (more likely) not. --Dean
  9. http://www.lifeextension.com/Lpages/2016/CRISPR/index Human Age Reversal at Harvard University When I incorporated the Life Extension Foundation, I envisioned a time when human longevity would not be constrained to a finite number of years. I was confident technology would emerge to enable science to gain control over pathological aging. When this biomedical turning point occurs, healthy life spans will extend beyond what anyone imagines today. Over the past two years, our hypotheses in the 1970s have emerged into scientific probability. I am pleased that Life Extension® was able to contribute in a small way to an emerging gene editing technique that may enable age reversal to transform soon into clinical reality. "Editing" Our Human Genome In Vivo As we age, genes that maintain cellular health and vitality are down regulated, while genes that promote disease and senescence become overexpressed. Once physicians are able to regulate or "edit" cellular genes, then youthful health may be restored to the entire individual. Articles in this month's issue of Life Extension® magazine describe a technology called CRISPR that has been developed and is being improved and extensively used at Harvard University and other institutions. Although most readers will find it difficult to comprehend, what's important to know is that CRISPR (clustered regularly interspaced short palindromic repeats) also offers a new way to rapidly transform senescent cells to regain youthful function and structure. CRISPR/Cas is a DNA cutting system originally developed in nature by bacteria as a way to destroy the DNA of viruses that frequently attack them. A natural version of CRISPR has been adapted by scientists to enable the reprogramming of cellular DNA to rid cells of unfavorable genetic changes. Once perfected, old cells may be rejuvenated and never age again. Programming Our Genes Like Computers The CRISPR/Cas system is empowering scientists to do very controlled gene editing, which means adding, disrupting or changing the sequence of specific genes. This has led to exciting new methods of transiently or permanently modifying gene action, either to increase or decrease the activities of targeted genes in a controllable way, potentially anywhere in the body and anywhere in one's complete set of genes and DNA (our genome). Since key features of aging are powerfully controlled by how genes are activated or inactivated (expressed or suppressed) in the body, these are critically important developments. Introducing the Harvard Pioneer of CRISPR Dr. George Church is a pioneer in the area of genome engineering and the development of gene editing tools based on the CRISPR/Cas9 system (referred to as CRISPR here). Dr. Church has already been able to reverse aging in human cells using CRISPR technology, and expects the first clinical trials of this technology to begin within as little as one year. In response to these breakthroughs, Life Extension®magazine sent Dr. Gregory M. Fahy to Harvard University to interview Dr. Church. We needed to clarify the opportunities for reversing human aging to save the lives of most of those reading this article now. These articles/interviews are written to enlighten our scientific supporters about this new age reversal modality. All readers should appreciate that this novel technology is being developed for the purpose of rapidly integration into the human clinical setting. Opening Comments by Dr. Greg Fahy… Is the End of Aging near at Hand? As a student of the aging process, I have been attending scientific meetings devoted to aging since the early 1980s, and have seen and heard a lot of very exciting things. But when I attended George Church's talk at a conference sponsored by Aubrey de Grey's SENS Foundation near the end of 2014, I realized that I had just heard the most remarkable talk in my life. Why? For three very simple reasons. First, as Dr. Church's talk highlighted, aging seems to be controlled to a large extent by the action of a rather small subset of your genes, and especially by master genes that control large numbers of other genes. Your genes, of course, are areas of your DNA that determine your eye color, your hair color, your sex, your height, and other characteristics of your body. But what is becoming increasingly clear is that genes also determine how you age—and maybe even whether you age. Second, Dr. Church described how technologies have advanced to the point where the activity of your genes—whether the genes are "turned on" (expressed) or "turned off" (repressed, or down regulated)—can increasingly be controlled. And this is not happening in just a test tube, but in whole bodies, and even in the brain. Dr. Church's focus is on CRISPR (clustered regularly interspaced short palindromic repeats) technology, which is a relatively new and particularly powerful method for adjusting gene activity in many different ways. CRISPR can "edit" or change genes for the purpose of correcting deleterious mutations, or to create deliberate mutations that can have positive effects (such as in knocking out the effects of pro-aging genes). So the implication is very clear: If aging is controlled by master genes, and if the activity of such genes can now be intentionally controlled, then we are beginning to approach the control of aging on a very fundamental level. And the same technology can be applied to the correction of many diseases as well, whether age-related or not. Finally, it would be of no use just to have the power to control aging if there was no will to utilize that power and move aging control to the clinic. Fortunately, Dr. Church wants his achievements to be rapidly translated into the clinical arena. He wants to make the control of aging a practical reality—and soon. And Dr. Church, as a highly distinguished professor of genetics and major figure at Harvard Medical School, is in an excellent position to make his wishes come true. In an interview with the Washington Post at the beginning of December 2015,1 Dr. Church said that his lab is already reversing aging in mice, and that human applications may only be a few years away. Dr. Church stated: "One of our biggest economic disasters right now is our aging population." "If all those gray hairs could go back to work and feel healthy and young, then we've averted one of the greatest economic disasters in history."1 He said he sees: "A scenario [in which] everyone takes gene therapy, not just curing rare diseases like cystic fibrosis, but diseases that everyone has, like aging."1 Dr. Church also described his personal passion in reversing human aging when he stated: "I'm willing to become younger. I try to reinvent myself every few years anyway."1 This new CRISPR technology may change the world, and our lives, as we know them. CRISPR is a technology originally developed by nature to fight viruses by cutting their DNA. Fortunately, it has now been modified by scientists to enable them to make specific controlled changes in targeted places in DNA. Once physicians are able to regulate or "edit" the DNA medically, then they can begin to work on restoring a state of youthful health in aging individuals. How serious is the promise of CRISPR? Consider the following: A newer version of CRISPR was recently inserted into a re-engineered virus delivery system and successfully used to correct the gene defect that causes Duchenne muscular dystrophy in a mouse model by either direct injection into a leg muscle or by infusion into the bloodstream, resulting in improvements in the muscles throughout the body and even in the heart.2 A leading scientific journal, Science, at the end of 2015, declared CRISPR to be the "breakthrough of the year," standing above all other scientific discoveries for 2015.3 On January 7, 2016, Dr. Church's company, Editas Medicine, filed papers to launch a $100 million IPO, and the company is already being backed by Google Ventures and the Bill and Melinda Gates Foundation.4 In short, in my estimation, the CRISPR revolution is a game changer, with staggering implications. If it all works out, nothing is going to remain the same. The prospects are as transformative as—if not more transformative than—such revolutions as the advent of the electric light, telephones, personal automobiles, airplanes, personal computers, the internet, and cell phones. Only this time, it's not just about how you live, but whether you live, and how long you will live: your health, your longevity, and the effect that health and longevity will have on your enjoyment of life. Will it really work? We will see. Opinions vary. Surely, there will be many tricks to learn and many twists and turns along the road ahead. And heavyweight scientist Craig Venter even says it will take 100 years to get it right. But George Church's lab is reversing aging in the laboratory today. So far, it's looking very promising, moving with incredible speed, and based on a very solid foundation of scientific observations about aging. My money is squarely on Church and others pursuing similar paths. The end of at least some critical aspects of aging may very well be near at hand. And the Life Extension Foundation is participating in this innovative and visionary project. The Life Extension Foundation has assisted Dr. Church by providing him data from a human super-centenarian research project that it funded. As Dr. Church mentions in his interview, studying super-centenarians may offer new insights into how human aging can be scaled back, once we have the right genetic tools to take advantage of those insights. Since the Life Extension Foundation is dedicated to improving healthy longevity, and since Dr. Church is working on pushing the ultimate limits of improving healthy longevity, with potentially open-ended possibilities ahead, this issue of Life Extension magazine features an extensive interview with Dr. Church that was conducted in his office at Harvard Medical School to enable us to present Dr. Church's work and thoughts to you. This interview is much more technical than many readers will be used to, and some may not be able to understand all of it, but we felt it was important to bring this important research breakthrough for the benefit of Life Extension® readers in the pursuit of healthy longevity. We hope you will be able to appreciate the substantive nature of what we think is likely to be a coming revolution that may touch your life in important ways. Controlling Human Aging by Genome Editing An Interview with George Church, PhD By Gregory M. Fahy, PhD Attempting to delay aging is now old hat. The new goal is to reverse it, not only in animals, but in humans. And age reversal is essential, as significant age-related disruption has already occurred in most people due to changes in our gene expression profiles. Gene expression patterns change with age. This influences the rate at which an individual ages, and also determines what senile disorders they are likely to contract. But innovative gene-editing methods based on a unique technology called CRISPR (clustered regularly interspaced short palindromic repeats) are now being successfully harnessed for use as an age-reversal therapy for humans. In response to these breakthroughs, Life Extension® magazine sent biogerontologist Dr. Gregory M. Fahy to Harvard University to interview Dr. George Church, who is a leading developer of cutting-edge CRISPR techniques. Here, Dr. Church explains remarkable opportunities for transforming human aging that may begin to unfold sooner than most have imagined. This interview with Dr. Church begins with a discussion on reversing cell aging by restoring youthful gene expression. Fahy: If aging is driven by changes in gene expression, then the ability to control gene expression using CRISPR technology could have profound implications for the future of human aging. Why do you think aging may be at least partly driven by changes in gene expression? Church: We know that there are cells that deteriorate with age in the human body and that we have the ability to turn those back into young cells again. This means we can effectively reset the clock to zero and keep those cells proliferating as long as we want. For example, we can take old skin cells, which have a limited lifetime, and turn them into stem cells (stem cells are cells that can turn into other kinds of cells) and then back into skin cells. This roundtrip results in the skin cells being like baby skin cells.5 It's as if my 60-year-old cells become 1-year-old cells. There are a variety of markers that are associated with aging, and those all get reset to the younger age. Fahy: That's fantastic. Does this mean that reversing skin cell aging in your face would allow you to rejuvenate your entire face? Church: If you rejuvenate at a molecular level, it doesn't necessarily mean that everything else rejuvenates. So, for example, if my face has a scar on it, it's not going to necessarily reverse that (although theoretically it's not out of the question). But we can reverse the tendency of your cells (and therefore of your whole body) to deconstruct when you reach your life expectancy. The Technology: How Genes and Their Expression Can Be Modified Fahy: So CRISPR has allowed you to reverse aging in human cells. CRISPR is an exciting technology. The CRISPR molecular machine—consisting of a protein and some associated RNA—can now be made in the lab or in our own cells and can change genes and gene expression. It's extremely powerful. Please tell us more about it. Church: CRISPR is the latest method for performing genome editing (editing of your whole set of genes). Its advantage is in part that a specific CRISPR tool can be created far more easily than other gene editing tools, and CRISPR is about 5 times more precise than other tools. The combination of the ease of construction, improved efficiency, and great flexibility makes it the most powerful gene editing tool to date. (See sidebar: Gene Editing with CRISPR) Fahy: Right now, with CRISPR, it is possible to modify, delete, insert, activate, and tone down or completely inactivate any gene, with considerable fine-tuning, either temporarily or permanently. (See sidebar: Gene Editing with CRISPR) Now let's talk about what this fantastic new ability could be good for. Specific Opportunities for Reversing Human Aging TFAM: Staying Energetic Indefinitely Fahy: There are several very exciting stories in aging intervention these days. In 2013, the Sinclair lab at Harvard came out with the revelation that the aging of mitochondria (which are the producers of usable energy within cells) is driven in significant part by reduced levels of one particular molecule in the cell nucleus: oxidized NAD (NAD+).6 The team showed that they could correct mitochondrial aging just by giving old mice nicotinamide mononucleotide (NMN), which is a vitamin-like substance that can be converted into NAD+, for one week. This resulted in phenomenal overall rejuvenation, including reversal of signs of muscle atrophy, inflammation, and insulin resistance. Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it? Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. (See sidebar: Gene Editing with CRISPR) Fahy: With this technique, you were able to increase TFAM levels in the cell by 47-fold. This resulted in restored ATP levels, increased NAD+, and an increased NAD+/NADH ratio. It also increased total mitochondrial mass and reversed several other age-related changes. Church: Yes. We have a number of ways to measure mitochondrial function and age-related losses of those functions. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections. GDF11: Achieving Overall Rejuvenation Fahy: Now, let's move on to GDF11 (growth differentiation factor 11), which is a protein and a type of youth factor that is present in the blood of young animals, but that declines with aging.7 Church: Yes, my lab is involved with the GDF11 story. We collaborate with Amy Wagers, a Harvard biologist famous for her work on heterochronic parabiosis, and her group, who are among the real pioneers for this. Fahy: GDF11 has been reported to rejuvenate the heart,8 muscles,9 and brain.10 It restores strength, muscle regeneration, memory, the formation of new brain cells, blood vessel formation in the brain, the ability to smell, and mitochondrial function. All of this is done by just one molecule. Infusing young plasma, which contains GDF11, into older animals also provides benefits in other tissues, such as the liver and spinal cord, and improves the ability of old brain cells to form connections with one another. How would you use CRISPR to make sure that GDF11 blood levels never go down? Church: The CRISPR-regulating GDF11 could be delivered late in life, which is exactly when such an increase would be welcome. If you really wanted to stay at a certain level, you might want to put in a GDF11 sensor to provide feedback so you could automatically control GDF11 production so as to lock in a specific GDF11 level. If necessary, you could recalibrate and fine-tune this maybe once every few decades with another dose of CRISPR. But yes, it's a great molecule, and we've got a handle on it. We are also doing a number of other projects with Amy now, dealing with a range of muscle diseases such as muscle wasting. We're working on possible treatments involving proteins such as myostatin and follistatin. Keeping Strong Muscles and Bones Fahy: Speaking of myostatin, the lack of which causes super-development of muscles, you mentioned in your 2014 SENS talk that you are interested in the possibility of enabling better muscle strength and less breakable bones. Is this another good treatment path for aging? Church: Muscle wasting and osteoporosis are symptoms of aging. The key to dealing with them is to get at the core causes, even if they're complicated. There are genes known to be involved in muscle wasting and genes that can overcome that. We're interested in these very powerful things, like growth hormone, myostatin, and the target for some of the new osteoporosis drugs, RANKL (Receptor activator of nuclear factor kappa-B ligand). Fahy: What about going beyond just correcting aging and actually super-protecting people by making them augmented with stronger bones or muscles than what they would normally have? Church: Rather than waiting until the muscles are wasting and then trying to correct the problem, or waiting until someone breaks a bone and putting a cast on, the idea is to make the muscles and bones stronger to begin with. Think of it as preventive medicine. You have to be careful, but there are people naturally walking around with much denser bones and much stronger muscles that have no particularly bad consequences, so we know such things are possible. Fahy: Can osteoporosis be reversed? Church: I would say osteoporosis definitely could be reversed. The process of bone building and bone breaking down is a regulated process that responds to conditions such as the good stress of standing or running. So yes, it's an example of something that's reversible. IKKβ: Reversing a Possible Whole-Body Aging Program Fahy: Let's move on to another aging process of potentially tremendous significance. According to a paper published in Nature,11 body weight, bodywide aging, and longevity are all controlled to a significant extent by the overexpression of one particular protein, IKKβ, in one highly specific place, the microglial cells in the medial basal hypothalamus in the brain. When this overexpression is prevented in mice, median and maximum life spans go up by 20% and 23%, cognition improves, exercise ability improves, and skin thickness and bone density also improves. In addition, collagen cross-linking is reduced and gonadotropin output goes up. If these improvements could be combined with the improvements caused by the other interventions we have discussed, the implications could be staggering. Church: Yes. What you're referring to is something that a certain school of thought thinks is aging programmed by the neuroendocrine system, by the brain, and the reason why mice start dying at two and a half years and bowhead whales start dying after 160 years. Fahy: Yes. And it's a particularly interesting problem because not only is it important in its own right, but it introduces the practical issue of fixing aging changes that arise in the brain. This part of the brain is protected from most things put into the bloodstream by the blood-brain barrier. Is it possible to get CRISPR technology through the blood-brain barrier and possibly address that particular pathway or other pathways in the brain? Church: The blood-brain barrier is greatly overstated in that there are many, many things that cross it, such as various drugs, viruses, and even whole cells. So, the answer is yes, we can deliver CRISPR across the blood-brain barrier. Telomerase: Heading Off Brain Aging and Cancer? Fahy: Telomerase is widely recognized as an enzyme that may prevent aging on the cellular level. But the lack of telomerase may also drive brain aging12 and cancer.13 Could CRISPR be used to replenish telomeres? Church: Yes, that certainly is feasible. The State of Gene Expression Is a Measure of Aging in Humans Fahy: Would you please explain epigenetics, and comment on evidence that there is an epigenetic clock of aging? Church: Epigenetics is essentially everything that controls gene expression. One component of epigenetics is DNA methylation, which consists of the addition of chemical entities called methyl groups to DNA at specific places. DNA methylation is important in part because it is a particularly easy component of the epigenome (the set of all epigenetic states) to measure. It turns out that DNA methylation changes with aging.14 In fact, the state of DNA methylation can predict the age of a person to within about three years.15 In principle, if you could change the biological age of a cell or of an organism to a younger state, and if those methylation sites (the sum total of which is referred to as the "methylome") are really reflective of age itself, then the methylome should change to the pattern you would expect at an earlier age. In other words, if aging itself changes, then this biomarker of aging should change in the same way. We use these methylation sites as a measure of how well we're doing in some of our studies where we're trying to get aging reversal, and it works extremely well. DNA methylation is very good for estimating the age of a person, and it can also be changed. Even though it's always linked to chronological age in normal life, in the world of aging reversal and epigenetic tinkering, you can change it, and the change is meaningful. Fahy: Not all 50 year olds are biologically 50. Some are biologically older and some are biologically younger. People age at different rates. Fascinatingly, these differences can be detected by the state of the methylome. If the methylome indicates a different age than your chronological age, you are really older or younger than your chronological age, and this was validated by a variety of other measures.14,16 Church: Yes, that is correct. The people who discovered the epigenetic clock of aging studied their outliers and found interesting correlations with them. There are multiple measurements for molecular level aging events, and they tend to reinforce one another. We don't know enough about connecting the dots between measures such as the methylome and aging factors such as GDF11, IKKβ, and TFAM, but if you're doing anything to reverse age, then the methylome should also reverse along with the reversal of aging. Fahy: Apparently, the DNA methylation state gets more chaotic as we age. For example, the methylation patterns of identical twins begin to diverge over time, more aberrant patterns being associated with greater pathology. This is consistent with a recent theory that attributes the lack of aging in some species ("negligible senescence") to a relatively stable pattern of gene expression over time, and normal aging to unstable and increasingly chaotic patterns of gene expression over time.17 But if you change gene expression back to what it should be, all of that variability should be reversible, right? Church: That's right. The variation in different parameters in any biological system increases when you get further away from the physiologically normal state. You can think of the methylation variance as another risk factor for aging and disease. How to Quickly Discover and Begin to Correct Currently Unknown Causes of Aging on the Gene Level Fahy: If aging is driven by changes in gene expression and those changes in gene expression can be reversed, then we need to be able to find all of the important age-related changes in gene expression as quickly as possible. How can this be done? Church: Gene expression results in each cell having specific RNAs and proteins, and these can be surveyed. You don't necessarily have to define every single RNA in a particular cell to understand that cell, but you can, and we have in fact developed a new method to do this that allows us to see all of the tens of thousands of RNAs in a single cell at one time, and to see the RNAs in neighboring cells as well. So now we can see how different cells relate to one another in context. This new method, called fluorescent in situ sequencing, or FISSEQ,18 allows us to count all the RNAs in a cell while simultaneously counting all of the RNAs in all of the cells it touches. Plus, we get the 3D coordinates for every RNA molecule in every cell. Fahy: That's unbelievable. How can you use this method to search for changes that are related to aging? Church: Suppose there are two different kinds of cell, and we want to know what gene expression states make them different from one another. We can first compare the two cells using FISSEQ in order to determine the differences in gene expression between them. Next, we can pick specific differences we think cause the cells to be different cell types, and change the expression of those particular genes in either or both cells using, for example, CRISPR, and see if we can change one kind of cell into the other. Even if we don't get it right the first time, we can take many guesses as to what the important RNAs are and just how much to tweak them until we do get it right. The same principle can be applied to any pair of cells. By comparing old cells to young cells, we can find out what makes an old cell an old cell, and how to turn an old cell into a young one. Fahy: Fantastic. Church: One of the problems with studying development and aging is that it takes a long time. But if we know the epigenetic state of all these different cells, no matter how many years apart they are, it only takes a few days to reprogram a cell and duplicate the effects of decades of slow change in the body, or reverse those effects. So in principle we could turn a young cell into an old one or an old cell into a young one because the only difference between them is epigenetics, or gene expression. Fahy: What other ways are there to identify powerful gene targets for intervention into human aging? Church: There are basically four good ways to find key gene targets. First, we can look at genes that underlie person-to-person variability in such things as low risk for viral infections, diabetes, osteoporosis, and so forth. The most extreme example here would be to compare normal people to super-centenarians, those who live to the age of 110 or older. They might have genes that are protective enough to find even with a small number of individuals, or even with a single individual. There are hundreds of genes that have small effects, but then way out on the end of the bell curve is something like the myostatin double null mutant or human growth hormone over/under production. Genes that have gigantic effects and completely dominate the effects of small environmental and small genetic influences are the right kind of gene to look for. The second way to find the best gene targets is to pick from discoveries made from basic studies like the GDF11 and TFAM that we talked about earlier. A third way is to use a specialized highly genomic strategy, such as mutating thousands of genes one by one to see if any of these mutations block aging, or using the FISSEQ method we discussed earlier. The fourth way to identify powerful gene targets is to compare closely related animals, one of which ages much more slowly than the other (like naked mole rats vs. rats). No matter where you get your lead, you don't have to worry about having too many hypotheses. Just use CRISPR to activate or inhibit that candidate gene and look for the biomarkers of aging reversal we discussed earlier. The idea is to see whether your change has an impact or not, and whether it acts synergistically with the other things that have been shown in the past to have an impact. Fahy: So if we saw something unusual or provocative in super-centenarians, we could create the same change in, for example, a normal human cell line and observe whether the right longevity pattern emerged. Church: Yes. Fahy: I've been told by James Clement, who is being funded by the Life Extension Foundation to do collaborative work with you on the genetics of super-centenarians (See sidebar: Life Extension Foundation Funding of CRISPR Research), that you might even be able to take super-centenarian gene expression patterns and put them into mice and see if the mice age more slowly. Church: Right. Our protocol will likely be to collect leads from the four different sources and try them out first on human cells. By going straight to human cells, we won't get into the trap of spending years working on mice, which is rather expensive, only to find out that it doesn't work in humans. We can actually do a cheaper and more relevant study in human cells, confirm them in mice, then test them in larger animals, and then in humans. I think that going from human cells to mice and back to humans is likely to save us time and money. Many human cellular testing systems are getting better and better, such as "organs on a chip" or organoids, which are getting to be more and more representative of in vivo biology. Eliminating the Tradeoffs of Intervening in Aging Fahy: Could the ability to target some genes and not others using CRISPR also make it possible to eliminate the side effects of some anti-aging interventions? For example, I'm working to show that it's possible to regenerate the thymus in humans and restore naïve T cell production using growth hormone. Although growth hormone does not cause cancer in adult animals or people, it slows down DNA repair in animals, which is an effect that is unrelated to the beneficial effects of growth hormone and to regenerating the thymus. Church: So you'd like to get rid of that effect on DNA repair while keeping the good effects. Fahy: Yes. If you can use CRISPR to go right to the genes of interest and not act through the usual pathways, which also lead to places you don't want to go, the unwanted effects should be avoidable, right? Church: Exactly. You could make a list of all the growth hormone targets and either pick the growth hormone targets you like and activate them selectively, or pick the growth hormone targets you don't like and block them so you could use growth hormone normally without inhibiting DNA repair. The Feasibility of Applying CRISPR Technology to the Whole Body Fahy: To reverse human aging, CRISPR technology will ultimately have to be applied in the whole body, and not just to cells in a test tube. How feasible is it to apply CRISPR technology in the intact body? Church: Gene therapy can be based on either ex vivo manipulations, in which cells are removed from the body, genetically modified, and then put back into the body, or on in vivo (within the body) methods, in which, for example, a modified virus might be used to carry a gene package into many different cells in the body. Each of these methods has pros and cons. There are viral and non-viral delivery systems that could be used to deliver CRISPR constructs and that will leave the blood vessels and go into the tissues. The delivery system could contain the CRISPR plus guide RNA plus the donor DNA (See sidebar: Gene Editing with CRISPR), or it could just comprise the CRISPR, guide RNA, and protein activator, and so on. But whether it's a viral delivery or a non-viral delivery method, the total mass of gene editing devices that has to be delivered will have to be considerable. But there is no rush, you can deliver them slowly. Fortunately, there are ways to manufacture biologicals that are dirt cheap. Things like wood and even food and fuel are all roughly in the dollar-per-kilogram range. If we could similarly make a kilogram of a viral delivery system and load it up with CRISPR, then it could become inexpensive enough to apply to the whole body. Fahy: Yes, a kilogram would be plenty! So, the viral delivery system contains a gene for CRISPR, a separate gene for the guide RNA, etc. When it delivers these genes to the cell, the cell makes the resulting proteins and nucleic acids, and all of the components simply assemble all by themselves in the cell, is that right? Church: Yes. Fahy: Which is the best CRISPR delivery system? Church: Adeno-associated viruses (AAV) are one of the favorite delivery systems right now because they can be nudged into going to tissues other than the liver (where many other delivery systems end up) more readily. This is an active field of discovery. It's moving quickly, and the CRISPR revolution just made it an even more desirable field to study. Safety Fahy: How selective can a virus be engineered to be for delivering CRISPR to just one cell class and not another in the body? Church: For every thousand cells of a particular type that you target, you might deliver your payload to one other cell of a different type that was not targeted. That should be good enough. Also, if you've got something that is required for cells in general, then it should be delivered to all cells. Even if you have something that is cell specific, it doesn't necessarily matter to which cells it is delivered. But in cases where it does matter, you can get the delivery right about 999 times out of 1,000 right now. Fahy: Could there be safety issues of having a one in 1,000 misdelivery rate? That would still come out to a lot of misdeliveries in a whole body. Church: It helps to remember that most drugs actually go to all the cells in your body. It would be a double standard to say that CRISPR has to be more specific than any previous drug. Safety also depends on what brand of "explosives" you're dealing with. It's like nitroglycerin versus TNT. If you make safety one of your top priorities, you're not going to be using something that can go awry, until you can make cell specificity very high. Fahy: Another point of importance for the safety of using CRISPR in the whole body is not just which cell it goes into, but whether it edits the right gene or not. How accurately can CRISPR be targeted within the genome? Church: In practice, when we introduced our first CRISPR in 2013,19 it was about 5% off target. In other words, CRISPR would edit five treated cells out of 100 in the wrong place in the genome. Now, we can get down to about one error per 6 trillion cells. Fahy: This must mean that the chance of a serious error is now low enough that it is very hard to measure, and far less than the spontaneous mutation rate. Church: Yes. And beyond this, there are ways to use small molecules as conditional activators to ensure that intended effects happen only in the correct cells. The combination of a totally safe small molecule activator and programmable targeting is unprecedented. Other checks can be put in as well for even greater safety. For example, once a viral payload gets inside the cell, it can make further decisions. It can essentially ask, "Am I in the right place?" before it acts. There's a whole field of molecular logic circuits that could be applied in order to avoid errors. Affordability Fahy: Is it going to be affordable for a human to reverse his or her aging process using this kind of approach? Church: If you look at the current price, it looks very unaffordable. There are about 2,000 gene therapies that are in clinical trials, but the only gene therapy that's approved for human use costs over $1 million per dose. You only need one dose, but at that cost it's obviously unattainable for most people. It's the most expensive drug in history, as far as I know. Fahy: What is that drug? Church: It's called Glybera®. It treats pancreatitis, a rare genetic disease. But sequencing the human genome used to cost $3 billion per person, and now has come down to just $1,000 per person, so I think getting from over $1 million down to the thousands shouldn't be that hard. Fahy: Another cost saver for aging intervention would arise if we could roll back aging significantly just by modifying five to 10 genes. That might get the overall cost down to something attractive. Church: Right. The combination of having to hit, say, a trillion cells in the whole body and 10,000 genes would be daunting. But if you can do a subset of cells and a subset of genes, then it becomes more feasible to make it affordable. Fahy: You have said that CRISPR therapy might have the potential to replace conventional drugs. Why is that? Church: A big advantage of CRISPR is that it offers better opportunities than conventional treatments for "putting knobs in" where there aren't any control knobs now. Right now, you have to be very lucky to have a potent drug that will do what you want it to do and nothing else. With CRISPR, we can be far more precise. How Many Aging Corrections Can Be Made at One Time? Fahy: If we know what to do and we can afford to do it, how quickly can we proceed to correct aging? What about simultaneous modification of, say, 10 different cell types in the body that were causing most aging changes? Could they all be modified at the same time? Church: "All" is a big word, but I think that many could be modified at once. This could be done by what we call multiplexing, using a mixture of viruses or delivery vehicles to enable many things to be done at one time. But you can also go slowly, starting with the highest priority tissues first and then going on to lower priority areas. Determining which tissues are the highest priority could vary with the patient's heredity, which might cause a particular tissue to be at higher risk for aging faster. Getting It to the Clinic: How Long Will It Take? Fahy: Using your most favorable pathway for intervention, how long will it take before a human trial might be possible? Church: I think it can happen very quickly. It may take years to get full approval, but it could take as little as a year to get approval for phase one trials. Trials of GDF11, myostatin, and others are already underway in animals, as are a large number of CRISPR trials. I think we'll be seeing the first human trials in a year or two. Fahy: Can you say what those trials might be? Church: I helped start a company called Editas that is aimed at CRISPR-based genome editing therapies in general.20 Some of those will be aimed at rare childhood diseases and others hopefully will be aimed at diseases of aging. We also have a company focused specifically on aging reversal that will be testing these therapies in animal and human models. Aging Intervention, the FDA, and the Dietary Supplement Model Fahy: Is the fact that the FDA does not recognize aging as a disease a problem? Church: The FDA is willing to regulate many symptoms of aging, such as osteoporosis, muscle decay, heart disease, mental agility, and so forth. It tends to be harder to prove a preventative than it is to prove a drug that cures an immediately and hugely harmful disease. And actually, since the FDA doesn't want you making unjustified health claims of any kind, they would have to take responsibility for regulating any health-related condition that one might want to make claims about. It doesn't have to actually be a disease. Fahy: It has been proposed that the FDA should just evaluate safety and not efficacy. How do you feel about that? Church: I really like that. The Internet will probably weed out the non-efficacious. The nutritional supplement market is a perfect example of safety being all that is needed for approval. You can get a nutritional supplement on the market just based on safety, but you can't get a prescription drug on the market just based on safety. It really should be the same rule. Fahy: The freedom to innovate and to create dietary supplements is what the Life Extension Foundation is all about. They fund all of my research in cryobiology, and they base their supplements on scientific literature. There are good effects of freedom and freedom to operate. Church: That's true. I'm just saying that there is a double standard for the FDA. The standards for supplements are different from the standards for new prescription drugs. Fahy: Perhaps if that were altered in favor of the standards for supplements, we'd have many more drugs and would all be a lot better off. Church: Yes. Focusing on safety is probably the right model. Fahy: Thank you, Dr. Church, for an amazing glimpse of the near future! References Available at: https: //www.washingtonpost.com/news/achenblog/wp/2015/12/02/professor-george-church-says-he-can-reverse-the-aging-process/. Accessed April 12, 2016. Available at: http: //today.duke.edu/2015/12/crisprmousedmd. Accessed April 12, 2016. Available at: http: //www.sciencemag.org/topic/2015-breakthrough-year. Accessed April 12, 2016. Available at: http: //www.dddmag.com/news/2016/01/google-backed-gene-editing-startup-files-100m-ipo. Accessed April 12, 2016. Studer L, Vera E, Cornacchia D. Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell. 2015;16(6): 591-600. Gomes AP, Price NL, Ling AJ, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7): 1624-38. Poggioli T, Vujic A, Yang P, et al. Circulating growth differentiation factor 11/8 levels decline with age. Circ Res. 2016;118(1): 29-37. Loffredo FS, Steinhauser ML, Jay SM, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013;153: 828-39. Sinha M, Jang YC, Oh J, et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science. 2014;344(6184): 649-52. Katsimpardi L, Litterman NK, Schein PA, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184): 630-4. Zhang G, Li J, Purkayastha S, et al. Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature. 2013;497(7448): 211-6. Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011;469(7328): 102-6. DePinho RA. The age of cancer. Nature. 2000;408(6809): 248-54. Peters MJ, Joehanes R, Pilling LC, et al. The transcriptional landscape of age in human peripheral blood. Nat Commun. 2015;6: 8570. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10): R115. Hannum G, Guinney J, Zhao L, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2): 359-67. Kogan V, Molodtsov I, Menshikov LI, et al. Stability analysis of a model gene network links aging, stress resistance, and negligible senescence. Sci Rep. 2015;5: 13589. Lee JH, Daugharthy ER, Scheiman J, et al. Fluorescent in situ sequencing (FISSEQ) of RNA for gene expression profiling in intact cells and tissues. Nat Protoc. 2015;10(3): 442-58. Mali P, Yang L, Esvelt KM, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121): 823-6. Sheridan C. First CRISPR-Cas patent opens race to stake out intellectual property. Nat Biotechnol. 2014;32(7): 599-601.
  10. Sthira

    On pursuing Biogerontology

    Your thoughts, if, say, hypothetically you were thinking of entering the fray. I copy and paste from: http://www.senescence.info/biogerontology_career.html How to Become a Biogerontologist senescence.info logo Biogerontologists study the biological process of aging at different levels and using different techniques and models. If you would like to do research on the biology of aging and/or you are a student thinking about pursuing a career in biogerontology then this brief essay is for you. Keywords: age-related diseases, gerontology, gerontologists, jobs By and large, biogerontologists work at research institutions, typically universities and laboratories, though some also work in the biotechnology industry--and a few companies research aging. The vast majority of biogerontologists have a PhD (or sometimes an MD or both), so if you want to become a biogerontologist you should be prepared to go to graduate and/or medical school. While it is possible to study aging in a private company or as a staff member of a research institution, the majority of influential biogerontologists have their own research group, like mine, at a research institution. Again, you can certainly contribute to research on aging in a variety of ways and even without making of it your main job, yet if you are serious about becoming a biogerontologist and doing independent research at the highest level then this usually implies developing an academic career. If you have an entrepreneurial spirit you could create, or help build up, a biotech company with some focus on aging. You could then do research, usually with translation to humans as a shorter-term aim than in academia, that has commercial value. Although there are a few people working on aging who followed this path, they are a minority and I know very little about entrepreneurship so cannot offer much advice on this--but wish you good luck. As such, this essay focuses on academia. How to develop a career in science is the subject of another essay of mine. Briefly, an academic career is highly competitive and usually entails having good grades in high school (in particular in science classes), getting a bachelor's degree with honors and later a doctoral degree (and maybe a master's degree in between, though I normally do not recommend it as top students can often enter a doctoral program without a masters), obtaining strong recommendation letters from advisors, and eventually developing a publication record, securing grants, and doing some teaching. If you are a student, you should have a counselor at your institution that can guide you through the process and there are also many resources on pursuing an academic career on the Internet. One major doubt of students is which topics they should study to prepare themselves for a career in biogerontology. Because aging is a biological process I would suggest that you include biology courses in your education. With the sequencing of the human genome and recent progress in the genetics of aging and longevity, I would also recommend some knowledge of genetics. Nevertheless, do not overestimate the importance of choosing the right courses and university. It does not make such a big difference because many different techniques and skills can be employed to study aging. There are physicists, physicians, engineers, biologists, geneticists, computer scientists, mathematicians, and many other different professionals studying aging right now. Therefore, my advice is for you to learn different skills, understand the science of aging, and focus on the area you find more exciting or more adequate to your personal situation. (As a side note, I would also recommend you develop good communication skills, both written and oral, as these are crucial not only in academia but in many other careers as well.) In the end, remember that who you are is more important than what you learn. To quote Einstein: "Creativity is more important than knowledge." Even though my opinion might be biased, I definitely think my essays on the biology of aging are an excellent introduction to anyone wishing to pursue a career in biogerontology. A briefer overview of gerontology is available as one of my papers (de Magalhaes, 2011). Nonetheless, I also suggest you take a look at my book recommendations since there may be other sources that better fit your personal taste. Lastly, there are occasional intensive courses on the biology of aging, such as the Molecular Biology of Aging course in Woods Hole, MA, USA. As an undergraduate, I would recommend you gain some research experience. This might also help you decide whether doing research is the career for you. For example, you can do an internship in a research group, like ours, and often your mentor or counselor will help you arrange this. I should note that I am always glad to help students aspiring to develop a career in aging research so if you wish to visit our lab or even spend some time here to see what we do just let me know. Once you become more familiar with research in general you will need to start reading academic papers. The main bibliographical database in the biomedical sciences is PubMed and you will need to become familiar with it at some point in your career, possibly in high school or the latest in college. At some point before going to graduate school, I would advise students to start identifying those researchers in the field whose work they most admire and sub-fields of particular interest. This can be done through publications, though often it is difficult for beginners to make sense of the massive archive of publications. Therefore, I would also advise you to look at the list I maintain of researchers working on aging, which includes links to the researchers' websites (if available) and links to PubMed that allow you to more quickly find relevant publications by each of the researchers. Similar to the point made above about how there is no right topic to study, there is no right school or even degree. Assuming your priority is research on aging then having a PhD has advantages over having an MD since it is difficult to balance research and clinical work, but more often than not this is a personal choice and many people enjoy clinical work. Regarding the choice of countries, this is certainly influenced by the mobility of each individual but a few points may be worth considering. The US and European systems are different in regard to graduate and medical schools. For example, graduate students in the US usually take longer to receive their PhDs. Mostly because of this, and please have in mind that I am an European, I normally would not recommend for an European to get his/her PhD in the US, but like many other suggestions in this essay this is often a personal decision. It is also possible to get a PhD from an European institution but do part or even most of the work in the US. Likewise, many people carry out most of their doctoral work in Europe or in the US but then receive their PhDs from institutions in other countries, often their native countries. Overall, working on aging has its challenges, such as the lack of adequate models of human aging and a lack of funding when compared to other biomedical disciplines. Salary-wise, in fact, working in academia is not the best career choice. Scientists usually do research because they love it, not because they want to become millionaires, though some scientists are also associated with industry which brings in extra income. Working in academia does have its advantages, such as schedule flexibility and creative freedom. Besides, since the field of aging is still largely mysterious with many unanswered questions, bright young minds have an extraordinary opportunity to make important contributions to science by studying aging. I hope you will be one of those minds. Please feel free to contact me if you have questions not covered in this essay or need any advice. Up to the Visitor's Resources Back to senescence.info Thank you for visiting my website. Please feel free to contact me if you have any questions, ideas, comments or suggestions. Copyright © 2007, 2008, 2012 by João Pedro de Magalhães. All rights reserved.
  11. All, Here is an interesting new study [1] (popular press story) that I appreciated as much for its data as its conclusions. In it, researchers identified a group of ~1400 "Wellderly" individuals - which they defined as: ndividuals who are >80 years old with no chronic diseases and who are not taking chronic medications. As you might imagine, these folks are pretty rare, and so they wanted to compare their genomes with those of an average population of elderly people. But first, they did an interesting thing - they compared the longevity of the siblings of the Wellderly cohort (who share a lot of genetics, and probably some lifestyle factors too, with the Wellderly folks) to see how their lifespan compares with the average US population. Here are the "survival curves" for the Wellderly siblings (red) vs. average folks (blue): As you can see, the Wellderly siblings had a more square mortality curve, but their survival curve wasn't shifted right - i.e. their "maximum lifespan" wasn't any longer than the average folks. Instead, both curves hit (near) zero around 100 years. Like the Wellderly themselves, their siblings appear to avoid / postpone the diseases of aging, and so do better in the "middle years" of elderliness (65-85), but beyond that have a mortality rate similar to the population as a whole. They then looked at the Wellderly folks' genetics. Interestingly, they didn't find their genomes to be particularly enriched with so-called "longevity genes" - those that have been identified as more common in centenarians or other very long-lived people. In other words, these folks are healthy agers, but don't seem to be blessed with genes for extreme longevity, which I thought was interesting. It suggests that at least to some degree healthy aging and extreme longevity are distinct, based both on the (sibling) survival curve data and their own genetics. Here is how the authors summarized this part of their findings: [O]ur results suggest that healthy aging is a genetically overlapping but divergent phenotype from exceptional longevity and that the healthy aging phenotype is potentially enriched for heritable components of both reduced risk of age-associated disease and resistance to age-associated disease. I'm curious what Michael would say, but it seems like this apparent distinction between disease avoidance and extreme longevity might undermine to some degree the SENS hypothesis - that aging simple is the accumulation of damage from the diseases of aging. Note: that is my potentially inaccurate summary of the SENS hypothesis... But what I found personally most interesting and helpful from this paper were two of their tables, listing the various genetic markers they tested for both longevity and Alzheimer's disease (AD). They quite explicitly listed the SNPs and which alleles of those SNPs are associated with longevity or AD. I've reproduced the two tables below, and added my own data, a friend's 23andMe data I have access to, and links to 23andMe so that any other 23andMe customers can check their own status for the corresponding SNPs. I've even added a tally at the bottom of each table with a genetic "score" - basically the number of "good" alleles one carries minus (in the case of the AD table) the number of "bad" alleles one carries. Although in the case of AD, it was the evil APOE4 allele that dominated - i.e. the biggest difference between the genes of the "Wellderly" folks and the average population was that the Wellderly were a lot less likely to carry APOE4 alleles. Anyway, here are the tables. First, the table with the SNPs and alleles previously identified (via other studies) to be associated with increased longevity. The "Longevity Allele" column shows that variant of the SNP that has been shown to be associated with increased longevity. The second column shows the gene the SNP is part of - as you can see many familiar names, including FOXO3, SIRT1, IL-6, IGF1, AKT (all of which I note have been associated with both CR and Cold Exposure in one way or another). The green letters show when I or "Person X" are carriers for the "good" longevity allele: Here are "live" links to the 23andMe page for each SNP so 23andMe customers can check their own results on these SNPs: https://www.23andme.com/you/explorer/snp/?snp_name=rs2802292 https://www.23andme.com/you/explorer/snp/?snp_name=rs1935949 https://www.23andme.com/you/explorer/snp/?snp_name=rs3758391 https://www.23andme.com/you/explorer/snp/?snp_name=rs5882 https://www.23andme.com/you/explorer/snp/?snp_name=rs1042522 https://www.23andme.com/you/explorer/snp/?snp_name=rs1800795 https://www.23andme.com/you/explorer/snp/?snp_name=rs2811712 https://www.23andme.com/you/explorer/snp/?snp_name=rs34516635 https://www.23andme.com/you/explorer/snp/?snp_name=rs2542052 https://www.23andme.com/you/explorer/snp/?snp_name=rs3803304 Here is the same sort of table, but this time for SNPs and Alleles associated with Alzheimer's disease and/or cognitive decline. Note, the last SNP in the table is the dreaded APOE4. As you can see from the p-value column, the APOE4 allele was far and away the most significant predictor of AD/cognitive decline, and the Wellderly had it less frequently that the general population (the column labelled "ITMI A2 Freq"). Also not that unlike the longevity SNPs, 23andMe didn't have data for many of the AD-related SNPs. Once again, the green letters show when I or "Person X" are carriers for the "good" allele (for avoiding AD) or and red letters show where one of us is a carrier for the "bad" allele (increasing risk of AD): Here are the direct links to 23andMe for the subset of SNPs from the table that were available (at least for me): https://www.23andme.com/you/explorer/snp/?snp_name=rs190982 https://www.23andme.com/you/explorer/snp/?snp_name=rs2718058 https://www.23andme.com/you/explorer/snp/?snp_name=rs1476679 https://www.23andme.com/you/explorer/snp/?snp_name=rs11771145 https://www.23andme.com/you/explorer/snp/?snp_name=rs11218343 https://www.23andme.com/you/explorer/snp/?snp_name=rs17125944 https://www.23andme.com/you/explorer/snp/?snp_name=rs10498633 https://www.23andme.com/you/explorer/snp/?snp_name=rs2075650 As you can see, for both the longevity SNPs and the AD SNPs, my score is a bit better than the score for my friend, "Person X" - so I got that goin' for me. And they are an unfortunate carrier of one APOE4 allele. ☹ To wrap up, the researchers also also found that a few of the Wellderly folks were enriched with an ultra-rare variants of a gene that seems to be especially protective against AD, called COL25A1 but I couldn't figure out what SNPs or alleles they were talking about. As always, these genetic marker studies need to be taken with a grain of salt. But it was fun to see where I and "Person X" stand regarding all these variants. I'd be curious if anyone else would be willing to share their data, or at least their "scores". --Dean ------- [1] Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.03.022 Whole-Genome Sequencing of a Healthy Aging Cohort Galina A. Erikson5, Dale L. Bodian5, Manuel Rueda, Bhuvan Molparia, Erick R. Scott, Ashley A. Scott-Van Zeeland, Sarah E. Topol, Nathan E. Wineinger, John E. Niederhuber, Eric J. Topol6, Ali Torkamani6 Free full text: http://www.cell.com/cell/pdf/S0092-8674(16)30278-1.pdf Summary Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype—healthy aging—to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. PMID: Unavailable
  12. Nickola from Singularity Webblog has a new interview with Dr. Michael Fossel, an expert on telomeres and telomerase. Quite an interesting interview. He has a new book, called the Telomerase Revolution and new company, called Telocyte, focused on extending telomerase to lengthen telomeres, and he claims, slow & reverse aging. Pretty big claims, and honestly he came across in the interview as a bit of a salesman... Unfortunately I can't seem to embed the video to start up at specific times, so I'm going to list the times of a couple interesting sections in the video, so you can jump ahead manually in the video embedded below: At 16:25 Nickola reads a single sentence summary of Fossel's "Telomere Theory of Aging" from his book. - He's basically saying that aging is a programmed result of changes in gene expression as the organism gets older, orchestrated by telomeres. When the relative length (not absolute length, he's clear to point out), of telomeres shortens, it changes which genes and especially how quickly genes get expressed, i.e. get read and translated into proteins. Without the right protein mix, bad things happen in cells, or more specifically, bad things continue to be generated, but they are no longer broken down at a fast enough rate. So they accumulate, and that is the major cause of cellular aging. So things like beta amyloid, or advanced glycation end products (AGEs), which can be broken down effectively in young animals, accumulate when telomeres get short and proteins aren't created to break them down. At 24:20 Fossel talks about why (teleologically) he thinks we age. That is, if its possible to keep the protein mix in cells "young" (via telomerase or some other method), why doesn't the body do this all the time? I was thinking he was going to say it's a tradeoff with cancer. But no, he doesn't. He says (to paraphrase) we age because the quicker a population turns over, the quicker it can adapt to a changing environment. For example, viruses that reproduce quickly can adapt very quickly via mutation. So organisms are designed to die off so that their mutated progeny can inherit the earth (or at least their parent's niche). I'm pretty dubious of this model... It doesn't seem to jibe with the "selfish gene" theory which seems pretty well established. But what do I know... At 33:40 and again at 40:30 he talks about the effectiveness (or lackthereof) of existing telomerase activator compounds, particularly astragalus. He says there is some evidence it works, but the supplements are either really expensive (like $200/mo) from reputable companies, or likely contain little astragalus if they are a lot cheaper. Josh Mitteldorf talks about telomerase and astragalus in several posts, like this one about a guy who has been taking high doses of astragalus since 2007. At 36:00 Fossel talks about the data in animals that suggests resetting telomere length can reverse aging as measured by quite a number of biomarkers. At 42:40 he talks about the potential side effects of lengthening telomeres, and specifically cancer. He makes an argument that cancer is unlikely to be significantly increased, but acknowledges there is the possibility that it would. His argument that it won't cause cancer is that extra telomerase upregulates expression of genes that repair DNA, so that will reduce cancer rate, balancing out with the extra ability for cells to divide. At 46:00 he says that's one reason they are targeting Alzheimer's Disease in their first clinical trial, because AD is a death sentence and these people are old anyway, so cancer won't have that long to proliferate and spread even if it is slightly increased by telomerase therapy. At 48:15 he talks about Liz Parrish and her "N=1" experiment with gene therapy, including telomerase activation. He understands her frustration with the slow progress of anti-aging research, but he is pretty skeptical that we'll be able to learn anything from her, because she is so young and healthy. He says she'll basically have zero credibility because of the way she's gone about it, without oversight, FDA approval, etc. He says they are going to go through the right FDA clinical trial process with their own efforts, at Telocyte. At 58:00 he talks about Aubrey and "longevity escape velocity". He says people 100 years from now will look back and identify the coming decade as the time frame when we cured aging. He says at 1:01:15 that there will be an "inflection point" that dramatically slows aging, whether you want to take the therapy or not, and whether there may be side effects or not, and that breakthrough will occur in the "next few years". He also disses Aubrey as not quite understanding the genetics involved in aging, and therefore being too conservative"by mistake", both in the timeframe for curing aging, and in the value of telomere therapy... At 1:02:00 he talks about the biotech company he started last year, Telocyte. They are planning a clinical trial to show they can "prevent and cure" Alzheimer's disease. If things go really well, he hoping to start a phase 1 clinical trial with a handful of AD patients around the end of 2016, have results 6 months later, and hopefully phase 2 trials shortly after that, if the phase 1 goes well. At 1:06:30 he talks about the clinical trial timeline in detail. At 1:10:20 he fields a question about how telomerase therapy can (or can't) deal with the other types of damage that accumulate with age. Like lipofuscin. He says "no problem", longer telomeres should do the trick. Not an entirely satisfying answer... At 1:15:40 he disses Aubrey again, as misunderstanding the relationship between senescent cells and aging. Dubious... At 1:17:40 if you look carefully he does the "finger twirl around the ear" gesture in reference to Aubrey, a gesture that is typically associated with someone being crazy, although with his words he says "Aubrey isn't thinking about the pathology [of senescent cells] well." At 1:19:50, he makes an interesting statement. He says that most people (hint - Aubrey) say that damage causes aging. He says that's backwards. Instead, aging permits damage to occur, or "aging causes damage". As we grow older, our telomeres shorten, causing changes in gene expression that results in poorer cellular repair and increased damage. Overall, as I said at the top, he comes across more as a salesman, rather than a researcher. He's very optimistic, and it would be great if he's right, and gets a chance to prove it, or be disproven, pretty soon... It seems like targeting AD might be a pretty good strategy to start with. --Dean
  13. Here is a cogent argument that aging researchers should focus more attention on the oldest of the old, both because it is a growing demographic and because the causing of aging (and eventual death) of the really old are different from the "young old", those in their 60s and 70s who are dying from the usual lineup of chronic diseases (heart disease, cancer, diabetes, etc), and so studying the really old could teach us a lot about the true causes of aging (or causes of true aging?): http://www.longevityreporter.org/blog/2015/9/8/anti-aging-old While the writer does mentioned gunk (amyloid) building up as part of the mechanism of aging in the very old (one of Aubrey's seven deadly sources of damage), overall his argument seems to be in somewhat interesting contrast to Aubrey De Grey's perspective (at least as I've seen him express recently). Aubrey seems to be focusing the efforts of the SENS research projects on reversing the damage that accumulates on the path to our common killers (e.g. genes from bacteria that can break down oxidized cholesterol which leads to heart disease), calling this accumulation of damage the true hallmark and cause of aging (my paraphrasing). Perhaps the author and Aubrey are not that far apart, but I've found Aubrey's blurring the line between aging "proper" and the "diseases of aging" very interesting. Intuitively Aubrey's perspective makes a lot of sense to me: accumulation of damage is just what it means to age, and when enough of it accumulates, it manifests itself as one of the diseases of aging and you die. But at the same time it seems like something other than the diseases of aging are very consistently limiting practical human lifespan to about 115-116 years (with Jean Calmet as an extreme outlier), as if there is something else going on in the background that will eventually get you even if the diseases of aging don't. --Dean
  14. Here is an interesting short blog post by our friend and evolutionary biologists, Josh Mitteldorf which he titles Aging is a Military Coup. In it he suggests two things, which I paraphrase thusly: Aging is not the passive process we used to think it was. Instead, aging is programmed into the body, and it is often a result of the body actively attacking itself in one way or another - commonly a result of the immune system response to inflammation. From a multi-level natural selection perspective, this self-destruction by individuals may be the way a community/society clears out its weaker members to make way for a new generation, and thereby promote the flourishing of the group. I don't think anyone can argue with #1 - aging, at least in the manifest forms Josh enumerates, does appear to be a very active, programmed response. But I'm much more skeptical about #2. It seems plausible, but far from proven. Here is how Josh describes it: If evolution found it necessary to regulate the individual’s life span for the larger good of the community or the ecosystem, there would be no need to invent a new and specialized death program. It would be far easier to coopt the body’s existing armies, and redirect them in a suicide mission. You can see where Josh gets the "military coup" metaphor in his title. But I think a better analogy is apoptosis. In Josh's model, the individual person is "self destructing" when they get old for the good of the community/society, in the same way an individual cell "self destructs" when it is damaged (via the process called apoptosis) for the good of body. Perhaps resources have been scarce enough in human history that it benefitted the group if older members died off to avoid consuming resources "unproductively". But it's not clear to me that there were enough long-lived, "parasitic" elders in our deep evolutionary history (when our ancestors rarely lived beyond age 30-40) to generate the kind of selection pressure in favor of "human apoptosis" that Josh postulates. Plus there is the "grandmother effect" which suggests older people (particularly women) may have been productive caregivers in a community even after their reproductive years. Regardless of whether his model is right or not, I don't believe that Josh thinks this human apoptosis is a good thing! --Dean
  15. Sthira

    Radiolab labs on mortality

    Good stuff, listened here yet? http://www.radiolab.org/story/91562-mortality/ I'd review it and tease it out like Dean does so much service here for us, but I'm not as eloquent as Dean, don't have his style and time, and I'd rather hear your thoughts and comments than my own silliness. "This hour of Radiolab: is death a disease that can be cured? "We filter the modern search for the fountain of youth through personal stories of witnessing death -- the death of a cell, the death of a loved one...and the aging of a society."
  16. Al Pater posted this review article [1] from way back in 2002 on the question of whether or not worldwide life expectancy is really beginning to level off, or is marching higher at the same 1/4 of a year per year rate that it has for the last 150 years. Here are two graphs from the paper, the first showing how striking and consistent the trend towards a higher lifespan has been, and how virtually everyone predicts it is going to level off (dashed red lines at the top): The authors postulate that the impression people have that lifespan is constantly on the verge of plateauing is an illusion with a few different causes. One interesting one is political. Politicians tend to low-ball when it comes to estimating future gains in life expectancy to make the cost of social programs, particularly those directly at the elderly like social security, medicare, look less costly and burdensome on the future. More interestingly, and with more evidence it would seem, they suggest the apparent leveling off in life expectancy gains is a result of the fact that the leading nation in life expectancy improvements keeps changing, with some countries (like the US) falling off the cutting edge, while other countries, like Japan, pick up the torch and push life expectancy higher at the same old rate of 1/4 of a year per year. So for the citizen in most countries, they fact is that lie expectancy improvements have levelled off. They give as evidence for this effect this graph: As you can see, Japan comes up after WWII to overtake the rest of the world in life expectancy, and keep us on the linear curve of life expectancy increases. Here are the authors' three rather bold assertions in the concluding paragraph of the paper: This mortality research has exposed the empirical misconceptions and specious theories that underlie the pernicious belief that the expectation of life cannot rise much further. Nonetheless, faith in proximate longevity limits endures, sustained by ex cathedra pronouncement and mutual citation (1, 8, 9). In this article we add three further lines of cogent evidence. First, experts have repeatedly asserted that life expectancy is approaching a ceiling: these experts have repeatedly been proven wrong. Second, the apparent leveling off of life expectancy in various countries is an artifact of laggards catching up and leaders falling behind. Third, if life expectancy were close to a maximum, then the increase in the record expectation of life should be slowing. It is not. For 160 years, best-performance life expectancy has steadily increased by a quarter of a year per year, an extraordinary constancy of human achievement. As I said - bold words. So that was in 2002. It's been almost a decade and a half since the paper was written. Have gains in life expectancy continued their "steadily increased by a quarter of a year per year" that the authors observe happening for the last 160 years? Nope - Not quite at least. Japan remains #1, and here is a graph of Japanese life expectancy that includes the period between 2002 through 2014: The paper reports in 2002 the life expectancy of a Japanese female was "almost 85 years", and in 2014 it was almost 87 years. So that is a life expectancy increase of 2 years in 12 years, or one sixth of a year per year, rather than the quarter of a year per year trend the authors point to. That equates to an average yearly shortfall in lifespan gains of 33% relative to the authors' prediction. Of course, this may be just a short-term deviation away from the long-term trend. Perhaps new advances in treatments or therapies for the diseases of aging (e.g. stem cell therapy, CRISPR-based gene therapy) will come along and keep us on the curve. It reminds me of the supposedly inexorable Moore's Law that futurist and immortality-optimist Ray Kurzweil likes to point to, namely that computer power (actually transistor count) doubles every two years, like clockwork, and has been for at least the last 40-50 years, and much longer than that if you ask Kurzweil. Unfortunately, I looks like we're falling off that curve too, according to this recent article in Nature (Feb '16): Next month, the worldwide semiconductor industry will formally acknowledge what has become increasingly obvious to everyone involved: Moore's law, the principle that has powered the information-technology revolution since the 1960s, is nearing its end. Similarly, at this point we seem to be slowing down rather than speeding up increases in life expectancy which would move us toward longevity escape velocity, where life expectancy increases by (at least) one year per year. --Dean ---------- [1] Science. 2002 May 10;296(5570):1029-31. No abstract available. Demography. Broken limits to life expectancy. Oeppen J, Vaupel JW. Free Full text: http://www.econ.ku.dk/okocg/VV/VV-Economic%20Growth/articles/artikler-2006/Broken-limits-to-life-expectancy.pdf Summary Is human life expectancy approaching its limit? Many--including individuals planning their retirement and officials responsible for health and social policy--believe it is, but the evidence presented in the Policy Forum suggests otherwise. For 160 years, best-performance life expectancy has steadily increased by a quarter of a year per year, an extraordinary constancy of human achievement. Mortality experts have repeatedly asserted that life expectancy is close to an ultimate ceiling; these experts have repeatedly been proven wrong. The apparent leveling off of life expectancy in various countries is an artifact of laggards catching up and leaders falling behind. PMID: 12004104
  17. Whenever I've heard Aubrey de Grey speak about defeating aging, he usually seems to downplay the potential impact on society and the planet that success in his project might have, and (to his credit) points out that it shouldn't be up to us to decide whether or not future generations should live a lot longer, and risk harming the planet by doing so - it should be up to them, and it is our moral responsibility to develop the tools to give them that choice. So it was with interest that I read this new study [1], sponsored by Aubrey's SENS research foundation, and the accompanying editorial by Aubrey [2], on statistical models of just what impact defeating aging in the coming century might have on human demographics and planetary sustainability. In [2], Aubrey says policymakers need to take into account the societal impact of defeating aging as projected in [1], but seems to downplay the magnitude of the impact, saying: [The projections from [1] show that] the actual, plausible trajectory of population growth following the arrival of effective rejuvenation biotechnologies only rather modestly exceeds the ‘‘base case’’ in which such technologies are never developed... Is "modestly exceeds" the base case scenario (no curing of aging) a fair way to characterize the projected impact of effective rejuvenation technologies described in [1]? I'm not so sure, and it doesn't seem like the authors of [1] are so sure either, at least by my reading. First, here are the two scenarios the authors of [1] using in their projects, based on differing mortality rates, one is the "base case" (people continue dying at a similar rate as today for the remainder of the century) and the other is the "Negligible Senescence" scenario (NegSens) in which scientists figure out how to stop aging in the next few years and it gets deployed over the next couple decades, at which point very few people will be dying: Based on this very low rate of people dying after the year 2040, the authors predict population growth based on three different fertility rates compared with the baseline scenario. In the baseline scenario, worldwide fertility rate drops from its current level of around 2.5 children per woman averaged over the entire world to 1.9 children per woman. In the (seemingly unrealistic) high fertility scenario, women start having more children than today once aging is defeated, with the fertility rate rising to 3.0, perhaps because they are living longer and are fecund for longer as well. In the mid-fertility scenario, the fertility rate is the same as the baseline scenario, i.e. 1.9 children per woman. This seems fairly reasonable it would seem, since childbearing / childrearing is an important part of many people's lives, giving them pleasure and their life meaning. In the low fertility scenario, fertility drops to 1.0 children per woman, "due to some combination of a reduced sense of self 'replacement' and 'old-age care' needs and of societal needs to limit fertility substantially to slow the rapid population growth of the underlying scenario." This last, low-fertility scenario may happen, but I'm skeptical societal attitudes about having kids will change that quickly, to the point that couples around the world on average only have a single child. But given these four scenarios (baseline and three NegSens fertility rates), here is the graph of population growth over time: The baseline agrees with most population projects demographers are currently making - namely that the global population will asymptote at around 10 billion around mid-century and then starts gradually declining. If women seriously curtail the number of kids they have, the low fertility NegSens scenario shows population growing only gradually to around 12 billion by the turn of the century - not too dramatic. But if women continue to have nearly two kids each, population will continue growing, to around 15 billion by the turn of the century. The high fertility NegSens scenario has population growing to a whopping 20 billion by the end of the century. In the remainder of the paper the authors pretty much ignore this high fertility scenario, as unrealistic and/or too depressing... One of the most interesting projections is the impact of the various scenarios on greenhouse gases. The authors point out that it is obviously quite sensitive to the mix of energy production methods (i.e. fossil fuels vs. renewables), but the authors project that neither the low nor medium fertility rates will substantially change carbon dioxide equivalents level in the atmosphere relative to the baseline scenario, with all three resulting in a pretty substantial increase in greenhouse gases over today's level of around 400 ppm to around 600 ppm by the turn of the century, or 800 ppm if we continue to use a lot of coal and other fossil fuels in our energy production mix. Those numbers are pretty depressing, given the temperature rise and climate effects the scientists are predicting unless we reverse the trend and keep greenhouse gases well below the current level of 400 ppm... In terms of worldwide hunger, the authors predict that with better food production / distribution methods, and a stable population, the baseline scenario will result in a dramatic reduction in hunger and starvation around the world by the turn of the century. But with a growing population as a result of defeating aging, we could see a world where hunger and starvation remain a problem of similar magnitude as today, as illustrated in the graphs below: Here is the most important paragraph from the author's conclusion: Finally, our results point to perhaps the greatest challenge facing a world of negligible senescence, those relating to the sustainability of our natural resources and biosphere. Given widespread concern that our economic way of life is already unsustainable, the potential addition of billions of people would concern many, especially given that this population (in the absence of negative feedbacks from environmental constraints) would see a GDP per capita 30% above the already substantial economic growth built into our Base Case. Energy demand levels, even with quite optimistic assumptions about efficiency gains and renewable contributions, would drive atmospheric CO2 levels above 600 ppm and, if coal were more heavily drawn upon without carbon sequestration, to 800 ppm or above. In the absence of food production technologies that are currently not on the forecast horizon, it might become nearly impossible to reduce the portion of the world's population that is undernourished. So in a sense Aubrey is right - global resources would be strained by defeating aging, but given a reasonably projection of fertility changes (dropping to 1.9 kids per woman worldwide), things won't go completely off the rails, at least by the turn of the century. Of course history won't end at 2100 (hopefully!), and in this 1.9 fertility rate scenario, population will continue to climb steadily, while the planet and its resources won't be getting any bigger... Perhaps by that time Elon Musk will have succeeded and we'll be colonizing Mars, so will have a lot more room and resources for humanity to expand. But I'm not holding my breath on that one, given the challenges of making Mars habitable and getting people there en mass. We live in interesting & challenging times, and it seem like things are only going to get more interesting & challenging. My primary reason for pursuing health / life extension is so that I can be around to see how things turn out - it promises to be quite a show! --Dean ------ [1] Technological Forecasting and Social Change, Volume 99, October 2015, Pages 77–91 doi:10.1016/j.techfore.2015.06.031 Opportunities and challenges of a world with negligible senescence Barry B. Hughesa, Randall Kuhnb, Eli S. Margolese-Malina, Dale S. Rothmana, José R. Solórzanoa Free full text: http://www.sciencedirect.com/science/article/pii/S0040162515001985 Abstract The development of anti-aging technologies could have dramatic implications for a world already challenged by population aging. We explore how the world might evolve given the development and deployment of technologies capable of nearly eliminating mortality and morbidity from most causes. We consider both the great benefits and some of the complex sociopolitical rebalancing resulting from such advances. We use the International Futures (IFs) long-term, multi-issue, global forecasting system in our analysis of the interactions among demographic changes, the related changes in health costs and government finances, shifts in labor force participation, resultant economic transformations, and the environmental sustainability of the dramatically-altered human demands that emerge. We find that the widespread deployment of anti-senescence technologies would cause populations to surge—making fertility rates an issue of tremendous social import—while a much larger, healthier, labor force would spur economic growth. But this is not a given; the cost of treating entire adult populations could prove unbearable to non-high-income economies without significant transfers within and across societies. In the absence of new transformative production technologies, life-pattern financing would require the virtual elimination of retirement and a major restructuring of government finances. Pressures on the environment would also greatly intensify. --------- [2] Rejuvenation Research. October 2015, Vol. 18, No. 5: 387-388 What Will a Post-Aging World Really Be Like? Finally, A Tool to Help Us Predict de Grey Aubrey D.N.J. Full text via sci-hub.io: http://online.liebertpub.com.sci-hub.io/doi/full/10.1089/rej.2015.1786 Excerpt: ... I am gratified to say that the findings reported in this article accord very strongly with my historical intuition. The conclusions are presented in a suitably cautious manner, incorporating stern warnings of the consequences if humanity fails to anticipate the impact that the arrival of these medicines will have on demands for food, sustainable energy, and, of course, the medicines themselves. However, that is indeed the purpose for which we sponsored this work—for two reasons. First, by setting out properly evidence-based projections through to the year 2100 of a few sample scenarios of how the various regions of the world will fare and what they will experience in a post-aging world, the paper lays to rest the far more pessimistic knee-jerk assumptions so vocally expressed by so many when the topic is discussed. The actual, plausible trajectory of population growth following the arrival of effective rejuvenation biotechnologies only rather modestly exceeds the ‘‘base case’’ in which such technologies are never developed, and it is vital that opinionformers and policy-makers should understand that fact if they are to make wise decisions concerning near-term investment in the long-term future.
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