Argument for Studying the Really Old

[Dean Pomerleau]

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

[Michael R]

The division between "aging" and the "diseases of aging" is a slippery one indeed: Aubrey has come to favor more or less obliterating it, whereas I still find it conceptually useful even if very problematic. The key thing is that particular diseases of aging are the late, pathological stage of the previously-silent accumulation of particular kinds of damage characteristic to an organ or tissue, so that that organ or tissue can no longer carry out its function, manifesting in a characteristic "disease of aging." I discuss all of this in a blog post on aging and diseases of aging.

(Super)cententarians: well, there's (at least) two things going on. Metabolism and its damaging side-effects are in themselves non-negotiable, although people vary modestly in the genes that modestly modulate the rate at which particular metabolic processes lay down particular forms of damage, and also add to that inescapable burden to varying degrees with accidents of the environment and with better or poorer lifestyles. When a person who lives long enough but shows no sign of a particular disease of aging, s/he hasn't accumulated enough damage from all causes to a particular organ or tissue to have developed the characteristic disease, but s/he has a very high and diffuse burden of damage across his or her entire system, making him or her incredibly vulnerable to any insult, even absent a specific disease diagnosis (and in reality, most centenarians do suffer with several – just fewer than you'd think from their age).

The other thing, however, is that the rate of deposition of damage, and the burden of such damage required to compromise organ or tissue function, does vary from one form of damage to another, such that some forms of damage take more or less time to manifest in disease. And while we have to be careful because the sample size is so small, there is a form of aging damage that is not only present but seems to be the cause of death in the majority of supercentenarians: in 2012, not long before his death, Steve Cole of the Supercentenarian Research Foundation reported that "Emerging SRF autopsy data continue to strongly suggest that supercentenarians die of amyloidosis-related causes (the primary cause of death in ~70% with the balance due to aspiration pneumonia)," and the great bulk of this does seem to have been wild-type TTR amyloidosis, whose most important and well-understood pathological consequence is senile cardiac amyloidosis.(1)

It is for this reason that SENS Research Foundation launched a project in 2012 to develop catalytic antibodies targeting senile cardiac (TTR) amyloid — a project which has recently reported substantial progress. In parallel, we initiated a project to develop a noninvasive blood test to diagnose the presence of TTR amyloid. The current assay requires the patient to undergo — and doctors to prescribe, and insurers to agree to fund — an invasive, expensive, and highly technical cardiac biopsy, followed by a workup for molecular identification of cardiac amyloid that few centers can even perform. A reliable, noninvasive, and inexpensive diagnostic assay would put an end to the gross (and always-too-late) underdiagnosis of senile cardiac amyloidosis(2) and other emerging disorders of wild-type TTR aggregates, and be an important tool to enroll patients in clinical trials for therapeutics like the catalytic TTR-targeting antibodies, and then to make use of it in the clinic. Happily, progress on the wild-type TTR/senile cardiac amyloidosis blood test is also proceeding apace.
 
References
1: Coles LS, Young RD. Supercentenarians and transthyretin amyloidosis: the next frontier of human life extension. Prev Med. 2012 May;54 Suppl:S9-11. doi:10.1016/j.ypmed.2012.03.003. PubMed PMID: 22579241.
 
2: Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014 Apr;2(2):113-22. doi: 10.1016/j.jchf.2013.11.004. PubMed PMID: 24720917; PubMed Central PMCID: PMC3984539.

[Dean Pomerleau]

Thanks Michael,

 

I highly recommend everyone read Michael's SENS blog post on aging vs. age-related disease. The video explaining the origins of cardiovascular disease is terrific!

 

--Dean

[Dean Pomerleau]

In the first post in this thread, I contrasted two perspectives on aging:

 

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.

 

So which is it? Do people always die of a "disease of aging", or is there such thing as dying of "old age"?  With this question in mind, I was very interested when I came across study [1] - courtesy of everyone's favorite, Dr. Greger  :) in this new video on the very early etiology of Alzheimer's disease. The researchers looked at the autopsy reports of 40 centenarians (average age of death = 102), to see what their reported cause of death was. Here's what they found:

 

An acute organic failure causing death was found in 100%, including cardiovascular diseases in 68%, respiratory illnesses in 25%, gastrointestinal disorders in 5%, and cerebrovascular disease in 2%. Additionally, centenarians suffered from several comorbidities (cardiac antecedents, neurologic disorders, liver diseases, cholecystolithiasis), which were not judged to be the cause of death.

 

Centenarians, though perceived to have been healthy just prior to death, succumbed to diseases in 100% of the cases examined. They did not die merely "of old age." 

 

So it looks like Aubrey may be right - that there is really no such thing as dying of "old age". Instead, the damage that accumulates over a lifetime eventually manifests itself as a disease or illness that finally does you in.

 

Of course, these were "only" centenarians, not supercentenarians. It could be that dying of "old age" only happens if you are fortunate enough to be one in six million people who live past 110 years. Even with CR, this seems pretty unlikely for any of us, unless radical life extension technology becomes available in the next few decades, then all bets are off...

 

--Dean

 

-------------------

[1] J Gerontol A Biol Sci Med Sci. 2005 Jul;60(7):862-5.

Do centenarians die healthy? An autopsy study.

Berzlanovich AM(1), Keil W, Waldhoer T, Sim E, Fasching P, Fazeny-Dörner B.

Author information:
(1)Institute of Forensic Medicine, University of Vienna, Austria.
andrea.berzlanovich@med.uni-muenchen.de

BACKGROUND: Our goal was to assess the prevalence of common causes of death and
the demographic variables in a selected population of centenarians.
METHODS: The autopsy reports and medical histories of all individuals > or =100
years, dying unexpectedly out of hospital, were gathered from 42,398 consecutive
autopsies, performed over a period of 18 years at the Institute of Forensic
Medicine, Vienna. These records were evaluated with regard to age and sex,
circumstances of death, season, time and the cause of death, as well as the
presence of any other comorbidity.
RESULTS: Forty centenarians (11 men, 29 women) were identified with a median age
of 102 +/- 2.0 (range: 100-108) years. Sixty percent were described as having
been healthy before death. However, an acute organic failure causing death was
found in 100%, including cardiovascular diseases in 68%, respiratory illnesses in
25%, gastrointestinal disorders in 5%, and cerebrovascular disease in 2%.
Additionally, centenarians suffered from several comorbidities (cardiac
antecedents, neurologic disorders, liver diseases, cholecystolithiasis), which
were not judged to be the cause of death.
CONCLUSIONS: Centenarians, though perceived to have been healthy just prior to
death, succumbed to diseases in 100% of the cases examined. They did not die
merely "of old age." The 100% post mortem diagnosis of death as a result of acute
organic failure justifies autopsy as a legal requirement for this clinically
difficult age group.

PMID: 16079208

[Greg Scott]

In the first post in this thread, I contrasted two perspectives on aging:

 

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.

 

 

This is a very interesting topic. I guess we will have to clarify the difference between a conventional disease and a quasi-disease triggered by a lethal background process of decay.

 

 

So which is it? Do people always die of a "disease of aging", or is there such thing as dying of "old age"?  With this question in mind, I was very interested when I came across study [1] - courtesy of everyone's favorite, Dr. Greger  :) in this new video on the very early etiology of Alzheimer's disease. The researchers looked at the autopsy reports of 40 centenarians (average age of death = 102), to see what their reported cause of death was.

 

Here's what they found:

An acute organic failure causing death was found in 100%, including cardiovascular diseases in 68%, respiratory illnesses in 25%, gastrointestinal disorders in 5%, and cerebrovascular disease in 2%. Additionally, centenarians suffered from several comorbidities (cardiac antecedents, neurologic disorders, liver diseases, cholecystolithiasis), which were not judged to be the cause of death.

 

Centenarians, though perceived to have been healthy just prior to death, succumbed to diseases in 100% of the cases examined. They did not die merely "of old age." 

So it looks like Aubrey may be right - that there is really no such thing as dying of "old age". Instead, the damage that accumulates over a lifetime eventually manifests itself as a disease or illness that finally does you in.

 

 

So accumulated decay manifests as a disease, and this is different from a disease caused by a single pathogen (micro-organism, poison, radiation, biochemical derangement whether genetic or induced, etc.)?

 

Of course, these were "only" centenarians, not supercentenarians. It could be that dying of "old age" only happens if you are fortunate enough to be one in six million people who live past 110 years. Even with CR, this seems pretty unlikely for any of us, unless radical life extension technology becomes available in the next few decades, then all bets are off...

 

--Dean

<snipped references>

Very interesting statistic (1 in 6 million living past 110 years). I'd like to see similar stats for ages above 90. Can you recommend a source for such stats?

 

Thanks for your interesting posts.

 

--

greg

[Dean Pomerleau]

Hi Greg!

 

So accumulated decay manifests as a disease, and this is different from a disease caused by a single pathogen (micro-organism, poison, radiation, biochemical derangement whether genetic or induced, etc.)?

 

 

I don't think and I don't think Aubrey would think there is a distinction to be made. Instead, we become more vulnerable to all those things you list as a result of accumulated damage as we age.

 

Very interesting statistic (1 in 6 million living past 110 years). I'd like to see similar stats for ages above 90. Can you recommend a source for such stats?

 

Here is the US 2010 Census report on Centenarians, which is a good source. Here is a cool graph of US centenarians from 1980 - 2010 (click to enlarge):

 

 

As you can see, this shows that about 1 in 5500 alive in the US today are Centenarians, compared with 1 in about six million for supercentenarian.

 

For a similar report on nonagenarians (90+ year olds), see this US census report. Below is Figure 1 from that report, showing that in 2010 there were about 2 million people over 90 in the US. Given the US population of about 300 million, that's about 1 in 150 people alive today.

 

 

So there is obviously a massively steep decline with each decade of life.

 

I just happened to come across this graph today, in this YouTube video called Living Beyond 100: Can We, and What If We Do? showing just how steeply survival drops off past 110:

 

 

Putting it all together, here is an estimate of the number of people on earth today (or in 2010) who've reached different extreme ages:

 

    90+  :   1 in               150

  100+  :   1 in            5,500

  110+  :   1 in     6,000,000

  111+  :   1 in   10,000,000

  112+  :   1 in   13,500,000

  113+  :   1 in   42,000,000

  114+  :   1 in 234,000,000

 

Note: this is NOT the same as your odds of reaching these ages. But it does give you a feel for just how unlikely it is to live a really long time. 

 

--Dean

 

 

[Mary Robinson]

The path from conception to adulthood is a carefully orchestrated symphony of gene expression changes.  It appears to me that these transitions continue throughout our lives. For instance, the transition into menopause in women is generally timed to happen within a narrow range of ages - too narrow to be the result of "wear and tear".

 

While damage seems to actually kill us, we also seem to turn off our repair functions as we age. Personally, I think the main cause of death is programmed in the genes. There is a species survival advantage to create continual replacements and kill off individuals over time. Minimally, this creates a constant adaptation to changing environments.

[Michael R]

All:

 

I guess we will have to clarify the difference between a conventional disease and a quasi-disease triggered by a lethal background process of decay.

That depends on what you mean by "a conventional disease." Atherosclerosis, cancer, Alzheimer's, Parkinson's, etc etc — all the diseases of aging — are triggered by a lethal background process of decay. Are they not "conventional diseases?"

 

There are many other disorders caused by lethal background processes of decay (aging) which aren't normally classified as diseases (sarcopenia; immunosenescence; primary age-related tauopathy; etc), but (again) that's really a matter of arbitrary convention.

 

 

 

So accumulated decay manifests as a disease, and this is different from a disease caused by a single pathogen (micro-organism, poison, radiation, biochemical derangement whether genetic or induced, etc.)?

 

I don't think and I don't think Aubrey would think there is a distinction to be made. Instead, we become more vulnerable to all those things you list as a result of accumulated damage as we age.

 

I actually think you (Dean) do think so, at least for microorganisms and poison: these are extrinsic, acute insults to the body, whereas diseases of aging are, again, exactly the tissue-specific manifestations of accumulated damage arising primarily from the side-effects of metabolic processes. We certainly become more vulnerable to all the above as we age, but a flu infection or poison still kills you the same way: it's just that you have less resilience against them. Radiation and biochemical derangement can either lead to acute death, or layer on to the inevitable cellular and molecular damage of aging, leading to "premature" onset of same.

 

Very interesting statistic (1 in 6 million living past 110 years). I'd like to see similar stats for ages above 90. Can you recommend a source for such stats?

As he indicates, Dean's data are really on prevalence, not incidence/odds at birth. I know I subsequently got a more direct source on this, but here are the numbers I once got from demographer of aging Leonid Gavrilov for roughly contemporary centenarians:

 

For USA men born in 1900 the chances to survive to age 100 years are:

 

At birth - 0.00203

At age 30 - 0.00283

 

For USA women born in 1900 the chances to survive to age 100 years are:

 

At birth - 0.0115

At age 30 - 0.0154

 

For both USA sexes born in 1900 the chances to survive to age 100 years are:

 

At birth - 0.00675

At age 30 - 0.00922

Of course, the odds for all but a few subsequent birth cohorts are higher.

 

The path from conception to adulthood is a carefully orchestrated symphony of gene expression changes.  It appears to me that these transitions continue throughout our lives. For instance, the transition into menopause in women is generally timed to happen within a narrow range of ages - too narrow to be the result of "wear and tear".

 

While damage seems to actually kill us, we also seem to turn off our repair functions as we age. Personally, I think the main cause of death is programmed in the genes. There is a species survival advantage to create continual replacements and kill off individuals over time. Minimally, this creates a constant adaptation to changing environments.

The "timing" of diseases of aging is also part of their very nature: by definition, it takes time for cellular and molecular damage to accumulate in tissues to sufficient degrees to erode redundancy to a sufficient degree as to impair function enough to be diagnosed as a 'disease.'

 

 

PD diagnosis is made based on cardinal motor signs (red) when approximately 50% of the dopaminergic neurons in the substantia nigra have been lost (threshold shown as the black dotted line). Individuals at high risk for PD (solid green line) will develop multiple premotor symptoms years before onset of PD motor signs; for individuals who will not develop PD (dashed green line), the joint prevalence of these symptoms remain at low level even at older age. [MR: the implication, of course, is that they would develop them if they lived long enough, absent rejuvenation biotechnology].

 

Menopause is pretty clearly a case of damage accumulation, albeit with some argument as to the precipitating cause. The symptoms are caused by a loss of feedback from the ovaries to the hypothalamus when the body ceases to produce eggs. The latter is either due to attrition of a supply of eggs produced antenatally, or that follicles are prevented from initiating new oocyte production by factors in the local environment of the niche due to structural damage, or by damage to the (putative) resident germline stem cells. The last of these was first suspected because of reports of young female cancer survivors who had been rendered menopausal by radiation or chemotherapy, but who subsequently exhibited restored ovarian function after haematopoietic stem cell transplantation.

[Michael R]

Table 4 of the report "Differences in life expectancy between those aged 20, 50 and 80 – in 2011 and at birth" from the UK Department of Work and Pensions shows "Chance of living from birth to 100, by year of birth" for reesidents of the UK. 0.3% of males and 1.1% of females (total population, 0.7%) born in the UK in 1912 lived to be over 100.

[Dean Pomerleau]

Table 4 of the report "Differences in life expectancy between those aged 20, 50 and 80 – in 2011 and at birth" from the UK Department of Work and Pensions shows "Chance of living from birth to 100, by year of birth" for reesidents of the UK. 0.3% of males and 1.1% of females (total population, 0.7%) born in the UK in 1912 lived to be over 100.

 

Michael,

 

Wow. That is interesting. The likelihood of reaching 100 as reported in that table (e.g. 0.7%, or 1 in 142, for someone born in 1912) is a heck of a lot higher than what one would naively assume from the population statistics - that "about 1 in 5500" people in the population are centenarians today. For someone born around when I was (1964), the table says that the likelihood of living to 100 is around 14%! Those are much higher odds than I'd ever imagined, and it makes me much more optimistic, particularly since I have a favorable FOXO3 variant.  :)

 

Not being a strong statistics person, I'm a bit confused about the source of such a big discrepancy between 1:142 and 1:5500. I guess the "1 in 5500" is misleading as a result of it being a measure of prevalence of centenarians in the entire population rather than incidence of centenarians in a particular subset of the population (e.g. only those folks born in 1912)? 

 

But hold on, this source [1] is much more pessimistic than your table. From the full text:

 

[F]ewer than 10% of women from the 1959 birth cohort are projected to reach age 90 years, and only 0.3% are projected to reach age 100 years. Another way of expressing this is that the likelihood of making it from birth to age 90 years is similar to the likelihood of making it from age 90 to 100 years. 

 

So this is saying a woman (and it would be lower for a man) born around when I was, has only a 0.3% (1 in 333) chance of reaching 100. Still a lot better than 1 in 5500, but far from the 14% (actually 15.6%, or nearly 1 in 6, for women born in 1959) suggested in the table you point to.

 

Any idea about the source of such a large disagreement? Your table is UK data and [1] is based on US census data, but I can't imagine that making much of a difference.

 

In many respects the table you point to seems too good to be true, suggesting a 1 in 6 chance of living to 100 for some who is around 50 today (actually maybe even higher, since I've made it this far and am still alive!).

 

Are they assuming major advances to geriatric medicine or something? What am I missing? 

 

--Dean

 

-----------

[1] Epidemiol Rev. 2013;35:181-97. doi: 10.1093/epirev/mxs013. Epub 2013 Jan 31.

The epidemiology of longevity and exceptional survival.

 

Newman AB, Murabito JM.

 

The field of the "epidemiology of longevity" has been expanding rapidly in recent

years. Several long-term cohort studies have followed older adults long enough to

identify the most long-lived and to define many factors that lead to a long life

span. Very long-lived people such as centenarians have been examined using

case-control study designs. Both cohort and case-control studies have been the

subject of genome-wide association studies that have identified genetic variants

associated with longevity. With growing recognition of the importance of rare

variations, family studies of longevity will be useful. Most recently, exome and

whole-genome sequencing, gene expression, and epigenetic studies have been

undertaken to better define functional variation and regulation of the genome. In

this review, we consider how these studies are leading to a deeper understanding

of the underlying biologic pathways to longevity.

 

Full text: http://epirev.oxfordjournals.org/content/early/2013/01/30/epirev.mxs013.full

 

PMID: 23372024

[Dean Pomerleau]

Todd Freitag gave a very good explanation over on Facebook for the confusion over longevity probabilities and population statistics.
He wrote :

The good news is that the odds of living to 90 are much better than 1/150 even without any further improvements in life expectancy. There's a big difference between the following two statements:

A) 1/150 people are currently over 90

B ) The odds of an individual person reaching age 90 is 1/150

Maybe an easier way to see it is to consider that the median age in the US is about 37 years old. That means 1/2 people in the US are over the age of 37. The odds of living past age 37 are much better than 50/50 though!

Half the people haven't reached 37 yet, but almost all of those who haven't eventually will. Similarly, a lot of people who aren't 90 yet will eventually get there.
 

Thank Todd!

 

--Dean

[Dean Pomerleau]

The Longevity Reporter on Facebook posted a link to this really cool, dynamic remaining lifespan simulation. You put in your gender and age, and it shows you a probabilistic simulation of how many more years you are likely to live, based on US Social Security Administration data. Here is a snapshot of my results, after letting the simulation run for a while (click to enlarge):

 

 

Its fun to watch, and to root for the balls to roll further out along the mortality curve! As a 50 year-old male, it says I've got about an 18% chance of living past 90, and a 1% chance of making a century. One of the 1000+ balls even fell into the bin at 108. I'm hoping to be that one!

 

--Dean

[Dean Pomerleau]

This seems like the right thread to post this report from the Pew Research Foundation about how the ranks of centenarians have been rising dramatically in the last several decades, and promise to do so even more dramatically between now and 2050. Here is the most relevant graph, showing number of centenarians worldwide is projected to grow by a factor of 8x, from around half a million to about 3.5 million, by 2050:

 

 

Much of the growth will be in developing countries, especially China. But the US isn't projected to do too badly either. Here is the projected centenarian counts by year broken down by country:

 

 

Eyeballing the graph, it looks like they are projecting the US to go from about 75K centenarians alive today to 378 living centenarians by 2050, a factor of 5x growth. Let's hope we can be among them - although I won't turn 100 until 2064, at which time there may be centenarians on every street corner. Then again, maybe we will have all uploaded our minds or perished in the singularity. ☺ It promises to be interesting times - I hope to see it and participate!

 

--Dean

[TomBAvoider]

Pretty embarrassing, if you ask me - Japan has a fraction of the population of the U.S., and yet is projected to substantially outpace the U.S. in the number of centenarians by 2050. Of course, we've learned to be somewhat skeptical about the Japanese centenarian claims, based on the apparently widespread fraud of not reporting old people dying so that the family can keep claiming financial benefits from pension and retirement payments (I don't know if they've resolved the problem by now, nor do I know if this phenomenon has been accounted for by these projections by the Pew Center).