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Here is something technical I've been wondering about for a while now. I'm hoping one of the resident experts on science of aging (Michael, James, Brian?) can help to clarify it for me.

 

Back in the old days, about a decade ago, it seems from my recollection that there was a distinction between the concept of "Intrinsic Aging" (IA) and the diseases of aging. IA was an inexorable process that wasn't well understood, other than that it proceeded in the background, accelerated over time (maybe leveling off at some extreme age), and eventually and almost inevitably leads to one or more of the diseases of aging, which are almost always what kills a person. People almost never die of "old age" per se, but some specific cause resulting from the body's inability to indefinitely keep itself in good repair.

 

Furthermore, under this model, certain interventions, like exercise or a healthy diet, were able to "square the mortality curve" and extend mean lifespan by preventing some of the damage associated with the diseases of aging, but they couldn't slow down the underlying IA process itself, and so couldn't extend "maximum lifespan" - which I understood to be something like the age an organism could reach if it wasn't killed off prematurely by a disease of aging.

 

But there was one intervention that was known to be different - calorie restriction. CR, it was said, could slow the rate of IA, sometimes quantified as "mortality doubling time" and hence it was able to extend maximum lifespan, not just mean lifespan. Nothing else anyone had discovered was able to do this.

 

Fast forward 10 years and it seems like the idea of IA isn't as popular or prevalent, at least as far as I can see.

 

Instead, aging is described by experts like Aubrey as the accumulation of damage, which Aubrey and company have compartmentalized into the famous seven categories. As an example, one such category is the accumulation of intracellular junk, like when macrophages swallow toxic byproducts of cholesterol which they can't effectively break down, leading to their accumulation in the walls of arteries and eventually atherosclerosis, the plaques in our arteries that are responsible for heart disease.

 

But the thing is, interventions like a healthy diet and exercise can impact the rate of accumulation of damage caused by at least some of these seven categories, including the accumulation of intracellular junk in the form of toxic cholesterol byproducts.

 

So while exercise and a healthy diet were previously seen as completely ineffective at slowing intrinsic aging, now it seems they can positively influence at least one of (actually several of) the underlying causes of aging - the accumulation of damage from the seven categories. And so it would seem they are capable of slowing what amounts to the aging process.

 

From this perspective, it would seem to me that exercise and a healthy diet would now have to be considered bona fide anti-aging interventions (albeit relatively narrow and therefore ultimately ineffectual ones), whereas they didn't used to be considered anti-aging interventions at all, at least by the formal definition used in the gerontology community.

 

So am I understanding this correctly and there has been a shift in what scientists believe aging amounts to, or am I missing something? More specifically, is intrinsic aging now an outdated concept? And as a corollary, is calorie restriction just a better (although only modestly better if you ask Aubrey) anti-aging intervention than a good diet or exercise because it is more comprehensive i.e. it obviates a wider range of damage categories, a wider range of damage types within a category and the degree of damage of a given type it prevents?

 

--Dean

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Your understanding of each individual fact or abstracted principle here is basically correct (or, I should say: "in line with mainstream biogerontological thinking and/or Aubrey's and my flavor of same"), and your confusion lies in just a few missing distinctions and pieces that need to be put together.

First, you've got a confusion on two different ways of talking about aging. When you say,
 

Back in the old days, about a decade ago, it seems ... [that] "Intrinsic Aging" (IA)... was [understood to be] an inexorable process that wasn't well understood, other than that it proceeded in the background, accelerated over time (maybe leveling off at some extreme age), and eventually and almost inevitably leads to one or more of the diseases of aging, which are almost always what kills a person. People almost never die of "old age" per se, but some specific cause resulting from the body's inability to indefinitely keep itself in good repair. ...

Fast forward 10 years and it seems like the idea of IA isn't as popular or prevalent, at least as far as I can see.

Instead, aging is described by experts like Aubrey as the accumulation of damage, which Aubrey and company have compartmentalized into the famous seven categories.


These are not "old" add "new" understandings of aging, but talking about aging in different categories. Your first description of IA is to some extent at the macro level in the organism, and to some extent at the level of demography: what happens to a population of aging organisms in the survival curve, and how that reflects the statistics on survival in an individual. Your second discussion of aging describes the specifics of the underlying mechanistic, structural basis of aging in the individual organism.

That is, the "inexorable process that wasn't well understood ... proceeded in the background, accelerated over time (maybe leveling off at some extreme age), and eventually and almost inevitably leads to one or more of the diseases of aging" is the accumulation of cellular and molecular damage in tissues of an the organism. The reason why aging is intrinsic is because the fundamental drivers of the accumulation of that damage are metabolic processes that are essential (intrinsic) to life: the damage wrought in cells and essential structural biomolecules by the byproducts of the reactive chemistry of life, and the long-term structural consequences of "decisions" made by the cells (such as apoptosis and senescence) that ensure near-term survival but have deleterious long-term consequences to the structural integrity (and thus, the function) of the tissues.

As I mentioned in a previous post,
 

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.


Now, it's absolutely true that
 

interventions like a healthy diet and exercise can impact [MR' highlighting] the rate of accumulation of damage caused by at least some of these seven categories, including the accumulation of intracellular junk in the form of toxic cholesterol byproducts.


However, they "impact" them by way of supernumerary addition to the sum of damage that is intrinsic to necessary metabolic processes. So, for instance, there is a background level of nuclear DNA mutations caused by things like errors in DNA replication during cell division and hits to the DNA by free radicals generated by metabolic processes. But of course, there are many extrinsic ways to add on to your body's burden of nuclear DNA mutations by lifestyle and environmental exposures that are completely or almost completely unnecessary and generally purely deleterious rather than part of your body's essential life processes, such as smoking and radiation exposure.

Similarly, as you say, you can impact the rate of accumulation of toxic cholesterol byproducts within arterial macrophages (the ultimate driver of atherosclerosis) by doing things that increase your circulating LDL cholesterol level (such as eating too much saturated or trans-fat) or increasing the oxidative stress in your arteries (by smoking). But, again, this is all in the way of unnecessary, extrinsic addition to the necessary, intrinsic processes that will drive the accumulation of such byproducts in arterial macrophages, because some level of circulating LDL cholesterol is needed to maintain your cell membranes and enable the synthesis of various hormones, and will persist under any lifestyle conditions, and some level of oxidative stress will be generated as part of immune function, inter- and intracellular signaling, etc.

This is why longevity runs in some families: because of variations in genes that regulate the intrinsic drivers of the accumulation of cellular and molecular damage: the the rate of cell division; the "default" level of circulating LDL; the "rheostat" of the cellular machinery regulating senescence and apoptosis; etc. Members of long-lived families have genes that cause them to accumulate moderately less aging damage over time than the great majority of the population, and as a result they are able to put off the diseases of aging into their eighties instead of their seventies.
 

under th[e "intrinsic aging"] model, certain interventions, like exercise or a healthy diet, were able to "square the mortality curve" and extend mean lifespan by preventing some of the damage associated with the diseases of aging, but they couldn't slow down the underlying IA process itself, and so couldn't extend "maximum lifespan" - which I understood to be something like the age an organism could reach if it wasn't killed off prematurely by a disease of aging.


Yes, exactly — and the key word here is "prematurely." Again, those lifestyle interventions are ways to avoid adding additional, extrinsic damage onto the intrinsic damage caused by essential metabolic processes, and not die prematurely of diseases of aging — diseases that will, however, eventually follow anyway from the intrinsic damage caused by essential metabolic processes. The reason why it's "premature" is exactly because leading a poor lifestyle causes more damage than the intrinsic rate of damage accumulation that you're stuck with because of the very processes of life (with some minor variation dictated by your genes), causing you to suffer that specific disease earlier than you (basically) have to.

The reason, in turn, why optimal lifestyle "squares the mortality curve" is because it eliminates all the things that would cause you to die prematurely of age-related disease. The reason why it doesn't impact maximum lifespan is because it doesn't touch the intrinsic limits to life caused by the intrinsic drivers of damage accumulation.

This is particularly noticeable inasmuch as individual poor lifestyle practices impact only one or a very few of the forms of cellular and molecular aging damage, while leaving others unaffected, which in turn causes them to increase the risk of only a subset of diseases of aging. So eating a lot of saturated or trans-fat impacts one form of intracellular aggregate, and a set of diseases linked to that damage (atherosclerosis, and ensuing heart attacks and stroke), but not eg. your risk of lung cancer, or even another cause of cardiovascular disease writ large (senile cardiac amyloidosis, which is driven by wild-type transthyretin aggregates). Similarly, smoking will cause you to suffer prematurely from atherosclerosis and lung cancer, but not breast cancer or Parkinson's disease (indeed, there is some evidence that smoking may delay the onset of Parkinson's, albeit that the compounds responsible for smoking's effects on cancer are different from the one that likely protects you against PD).

By definition, then, to extend maximum lifespan, you have to get at those intrinsic drivers of aging — and you have to reduce all of them to some degree, because even if you were somehow able to dramatically reduce the intrinsic rate of nuclear DNA mutation accumulation, you would still develop atherosclerosis and die of a heart attack or stroke at exactly the same time you were already "scheduled" to do unless you also affected the rate of accumulation of toxic cholesterol byproducts in arterial macrophages — and so on down the line. This is why measuring maximum lifespan is the gold standard for empircally evaluating whether an intervention affects aging or not: the fact that things like Calorie restriction, mutations in the IGF-1 signaling pathway, true methionine restriction, and rapamycin increase maximum lifespan tells you that they are getting at all of the drivers of degenerative aging at once, and doing so to the proportion that they extend maximum lifespan.

And this is true even if you don't really understand (as we certainly didn't until recently, and still only very partially do) the mechanistic details of how they are affecting those drivers, or even what those drivers are. Thus Clive McCay could say with confidence in 1939 that
 

These results in combination with those of the earlier report (McCay, Crowell and Maynard, '35) indicate that the method of retardation affords a useful technic for studying aging. Animals that are relatively very old become available for study. Furthermore, the parts of the body that age in a normal animal can be compared with those of retarded animals that are destined for a much longer span. This affords a tool for investigating the systems that break down in the normal process of aging.


... even though he was completely ignorant of the cellular and molecular basis for the phenomenon he was observing. Indeed, it was exactly by doing what he suggests that the bulk of such cellular and molecular damage was identified in the first place.
 

From this perspective, it would seem to me that exercise and a healthy diet would now have to be considered bona fide anti-aging interventions (albeit relatively narrow and therefore ultimately ineffectual ones), whereas they didn't used to be considered anti-aging interventions at all, at least by the formal definition used in the gerontology community.


They aren't, for reasons that I trust you'll now understand more clearly.

Reference
McCay CM, Maynard LA, Sperling G, Barnes LL: Retarded growth, lifespan, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. J Nutr. 19 Jul;18(1)1–13.

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Thanks Michael. Your response was very helpful, and I do understand better now. I'm not sure I agree with this statement though:

 

However, [diet and exercise] "impact" [the causes of aging] by way of supernumerary addition to the sum of damage that is intrinsic to necessary metabolic processes. So, for instance, there is a background level of nuclear DNA mutations caused by things like errors in DNA replication during cell division and hits to the DNA by free radicals generated by metabolic processes.

 

What I think you are suggesting in this passage is that a bad diet and lack of exercise can add to the intrinsic damage being done to the body as a natural part of metabolism, but that these intrinsic insults continue unabated regardless of our lifestyle choices.

 

While I agree that some damage accumulation from basic metabolism is inevitable, it seems to me that a good diet and engaging in exercise can not only reduce/eliminate additional damage, but actively work to reduce the amount of intrinsic damage that is occurring. I know you're skeptical of hormesis, but can't, for example, a good diet ramp up our bodies defenses and repair mechanisms by challenging it with mildly toxic compounds, i.e. xenohormesis? This diagram seems to suggest that plant phytochemicals like curcumin and ECGC can impact several of the aging-related pathways in the same ways as calorie restriction:

 

post-7043-0-77847800-1441567273.jpg

 

If this is correct, it (still) seems to me that diet (and extrapolating, exercise) are bona fide anti-aging interventions. They just are not as effective anti-aging interventions as CR because they don't cover as many of the multiple damage types, and/or don't reduce the damage as well as CR does. Thus the distinction is more a matter of degree, rather than kind. Is this right or am I still confused in this regard?

 

BTW, has anyone ever thought about aging as analogous to the video game Tetris? For anyone who has never seen or played it, you can give it a try here. Its simple but very addicting. Here is a screenshot to give you a flavor for it:

 

Tetris_screen007_vf1.jpg

 

 

Here is a video of gameplay if you want to get a better feel for it, although this person is a good player so they never die :)xyz :

 

 

In the game, different shaped pieces fall from the top of the screen, and it is your job to deal with them - pack them together in neat little rows at the bottom of the screen despite their irregular shapes. Whenever you completely fill a row (without gaps), that row disappears, creating more room between the top of the screen and the growing stack of shapes at the bottom. If/when the stack grows to the top of the screen, its GAME OVER - you're dead.

 

The falling pieces with different shapes are like the different forms of intrinsic and extrinsic damage the body is bombarded with continuously. Some shapes are more irregular than others, making them harder to 'detoxify' (i.e. fitting them neatly and without gaps into the stack), analogous to really bad toxins, like those in cigarette smoke. Others are more compact and less jagged, making them easier to fit in, and often beneficial for clearing rows. These can be considered the equivalent of antioxidants or other detoxifying agents. The height of the stack is equivalent to the amount of damage that has accumulated so far, i.e. how much the organism has aged, in this analogy.

 

When you are young (i.e. the stack is short), it is easy to figure out how to handle (detoxify) all the damaging compounds and environmental insults being hurled at you (i.e. how to stack the shapes neatly to eliminate rows). But as the stack grows (as you age), it becomes harder and harder to fit in the shapes as they come flying at you - the damage done so far (that has increased the height of the stack) makes it harder to react appropriately to new damage. In other words, aging accelerates as we age because of damage to the very systems designed to detoxify and repair new damage as it arrives, in a viscous cycle. Eventually the onslaught of damage becomes too much for the body to handle, the stack grows faster and faster until it reaches the top, and you die.

 

This seems to me like a pretty good analogy for they way I now understand the aging process to happen. Yes, no, maybe?!

 

--Dean

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All,

 

In the Tetris analogy for aging described above, it gets harder to cope with each new sling/arrow that gets thrown one's way as we age (as the 'game' progresses), and this occurs in a non-linear (exponential or geometric?) progression. In other words, as the stack of pieces gets taller and taller, you have less and less time to cope with each new piece that falls. As a result you are increasingly likely to make a mistake in coping with each new falling piece. And when you make a mistake, the stack gets even taller, exacerbating your coping problem even further. As a result, the "end game" tends to go very quickly - once the stack gets taller than a certain height, you're inevitably going to die in short order.

 

From my understanding, this is a pretty well accepted model of how aging works - damage begets poorer repair which begets more damage, in a vicious, accelerating cycle. This new paper [1] posted by Al Pater (thanks Al!) provides empirical data from humans (or at least Canadians :)xyz) to support this model. The authors followed at a group of people of varying ages for 16 years, and counted up the amount of 'damage' they'd accumulated  - what they call the frailty index (FI) every couple years. The full list of 92 items on the FI can be found in [2], and are listed at the bottom of this post, but here are a few representative examples to give you a feeling for them:

 

2* SLEEPCH sleep changes
3* MOBILITY mobility impairment
4* MEMORY difficulty with memory
5 MOOD difficulty with mood
9* GROOM difficulty with grooming
28* GASTRO gastro-intestinal complaints
48* TREMORAC neur exam: tremor/action
74 FJUDGEME impaired judgement
81 HEART heart and circulation problems
86 BLADDER lose control of bladder

 

As you can see they span the gamut of bad things that can happen to someone as they age... The researchers simply computed the fraction of these items each subject reported or experienced as a function of their age, to see the time course of this damage accumulation. Here is the money graph from the full text:

 

9iNopAr.png

 

As you can see, the FI is a non-linear function of age - the older a person gets, the faster the rate of damage accumulation, as represented by the fraction of frailty symptoms they report. From the data, the author's computed that the mean doubling time for frailty items is 15 years - every 15 years on average the number of frailty symptoms a person reports doubles.

 

From another paper [3] by the same others, here is how they characterize what's going on in aging:

 

While different individuals face a variety of different health problems, there is a common denominator—the number of health problems increases with aging and increases faster in those individuals whose health is poor (Yashin et al. 2007a; Kulminski et al. 2007). Ageing develops gradually and starts from small changes in health (Kirkwood 2005) which accumulate across the adult life course (Rockwood et al. 2011). While many of the variables, when considered in isolation from each other, have only small effects on health, their cumulative effect becomes significant (Mitnitski et al. 2001, 2002; Kulminski et al. 2007). These cumulative effects can be quantified by combining health related variables (either biological or clinical, including even those self-reported) in a so-called fitness/frailty index or more often just a FI. This term reflects its extensive use in medicine, where the increased vulnerability of older adults to adverse outcomes is referred to as frailty (Fulop et al. 2010; Rockwood and Mitnitski 2011; Clegg et al. 2013).

 

In short, as people accumulate damage with age, they aren't able to cope with new stresses as effectively, so the new damage accumulates at an accelerating rate, apparently doubling about every 15 years, according to the date from these researchers. Interestingly, this frailty doubling time (15 years) is only about half the estimated human mortality doubling time (8 years). I'm not sure what would explain this difference. Maybe Michael would know.

 

--Dean

 

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

[1] Biogerontology. 2016 Feb;17(1):199-204. doi: 10.1007/s10522-015-9583-y. Epub 2015 May 14.

 

The rate of aging: the rate of deficit accumulation does not change over the adult life span.

 

Mitnitski A, Rockwood K.
PMID: 25972341

Full text: http://link.springer.com.sci-hub.io/article/10.1007/s10522-015-9583-y

 

Abstract

 

People age at different rates. We have proposed that rates of aging can be quantified by the rate at which individuals accumulate health deficits. Earlier estimates, using cross-sectional analyses suggested that deficits accumulated exponentially, at an annual rate of 3.5 %. Here, we estimate the rate of deficit accumulation using longitudinal data from the Canadian National Population Health Survey. By analyzing age-specific trajectories of deficit accumulation in people aged 20 years and over (n = 13,668) followed biannually for 16 years, we found that the longitudinal average annual rate of deficit accumulation was 4.5 % (±0.75 %). This estimate was notably stable during the adult life span. The corresponding average doubling time in the number of deficits was 15.4 (95 % CI 14.82-16.03) years, roughly 30 % less than we had reported from the cross-sectional analysis. Earlier work also established that the average number of deficits accumulated by individuals (N), equals the product of the intensity of environmental stresses (Lambda) causing damage to the organism, by the average recovery time (W). At the individual level, changes in deficit accumulation can be attributed to both changes in environmental stresses and changes in recovery time. By contrast, at the population level, changes in the number of deficits are proportional to the changes in recovery time. In consequence, we propose here that the average recovery time, W doubles approximately every 15.4 years, independently of age. Such changes quantify the increase of vulnerability to stressors as people age that gives rise to increasing risk of frailty, disability and death. That deficit accumulation will, on average, double twice between ages 50 and 80 highlights the importance of health in middle age on late life outcomes.

 

KEYWORDS:

Aging; Deficit accumulation; Frailty; Longitudinal analysis; NPHS; Recovery time

 

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

[2] Scientific World Journal. 2001 Aug 8;1:323-36. 

 

Accumulation of deficits as a proxy measure of aging.

 

Mitnitski AB(1), Mogilner AJ, Rockwood K.

 

Author information:
(1)Department of Mechanical Engineering, Ecole Polytechnique, Montreal, Quebec
H3C 3A7. arnold@grbb.polymtl.ca

 

This paper develops a method for appraising health status in elderly people. A
frailty index was defined as the proportion of accumulated deficits (symptoms,
signs, functional impairments, and laboratory abnormalities). It serves as an
individual state variable, reflecting severity of illness and proximity to death.
In a representative database of elderly Canadians we found that deficits
accumulated at 3% per year, and show a gamma distribution, typical for systems
with redundant components that can be used in case of failure of a given
subsystem. Of note, the slope of the index is insensitive to the individual
nature of the deficits, and serves as an important prognostic factor for life
expectancy. The formula for estimating an individual's life span given the
frailty index value is presented. For different patterns of cognitive impairments
the average within-group index value increases with the severity of the cognitive
impairment, and the relative variability of the index is significantly reduced.
Finally, the statistical distribution of the frailty index sharply differs
between well groups (gamma distribution) and morbid groups (normal distribution).
This pattern reflects an increase in uncompensated deficits in impaired
organisms, which would lead to illness of various etiologies, and ultimately to
increased mortality. The accumulation of deficits is as an example of a
macroscopic variable, i.e., one that reflects general properties of aging at the
level of the whole organism rather than any given functional deficiency. In
consequence, we propose that it may be used as a proxy measure of aging.

 

PMID: 12806071

 

---------

[3] Biogerontology. 2013 Dec;14(6):709-17. doi: 10.1007/s10522-013-9446-3. Epub 2013

Jul 17.

Assessing biological aging: the origin of deficit accumulation.

 

Mitnitski A(1), Song X, Rockwood K.

 

Author information:
(1)Department of Medicine, Dalhousie University, Suite 229-5790 University Ave.,
Halifax, NS, B3H 1V7, Canada, arnold.mitnitski@dal.ca.

 

The health of individuals is highly heterogeneous, as is the rate at which they
age. To account for such heterogeneity, we have suggested that an individual's
health status can be represented by the number of health deficits (broadly
defined by biological and clinical characteristics) that they accumulate. This
allows health to be expressed in a single number: the frailty index (FI) is the
ratio of the deficits present in a person to the total number of deficits
considered (e.g. in a given database or experimental procedure). Changes in the
FI characterize the rate of individual aging. The behavior of the FI is highly
characteristic: it shows an age specific, nonlinear increase, (similar to
Gompertz law), higher values in females, strong associations with adverse
outcomes (e.g., mortality), and a universal limit to its increase (at FI ~0.7).
These features have been demonstrated in dozens of studies. Even so, little is
known about the origin of deficit accumulation. Here, we apply a stochastic
dynamics framework to illustrate that the average number of deficits present in
an individual is the product of the average intensity of the environmental
stresses and the average recovery time. The age-associated increase in recovery
time results in the accumulation of deficits. This not only explains why the
number of deficits can be used to estimate individual differences in aging rates,
but also suggests that targeting the recovery rate (e.g. by preventive or
therapeutic interventions) will decrease the number of deficits that individuals
accumulate and thereby benefit life expectancy.

 

PMCID: PMC3847281
PMID: 23860844

 

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

Frailty Index Items (from [2]):

 

1 CLOUDING clouding/delirium
2* SLEEPCH sleep changes
3* MOBILITY mobility impairment
4* MEMORY difficulty with memory
5 MOOD difficulty with mood
6* GOUOUT difficulty with going out
7* COOKING difficulty with cooking
8* GETDRES difficulty with getting dressed
9* GROOM difficulty with grooming
10* BATH difficulty with bath
11* TOILET difficulty with toileting
12 URINE incontinence of urine
13 STOOL incontinence of stool
14 ONSET onset of symptoms (gradual or abrupt)
15 SAD feel sad, blue or depressed
16 REST resting tremor
17 ACTION action tremor
18 CHOREA dyskinesias/chorea
19 AKINESIA akinesia
20 HXSTROKE history of stroke
21 HEADACHE headaches of recent onset
22* LOSSVISI chronic visual loss
23* LOSSHEAR difficulties with hearing
24* ARTERIAL arterial hypertension
25 CARDIAC cardiac symptoms
26 RESPIRAT respiratory complaints
27 MALIGNAN history of malignancy
28* GASTRO gastro-intestinal complaints
29* URINARY urinary complaints
30 HISTHYRO history of thyroid disease
31* HXDM history of diabetes mellitus
32 NECH physical exam: head and neck (normal, abnormal)
33 THYROID physical exam: thyroid
34 BREAST physical exam: breast
35 LUNG physical exam: lungs
36* VASCULAR physical exam: cardiovascular
37 CAROTIDS physical exam: peripheral pulses
38 ABDOMEN physical exam: abdomen
39 RECTUM physical exam: rectum
40* SKINCLIN physical exam: skin
41 SUCKING neur exam: sucking, release sign
42 SNOUT neur exam: snout, release sign
43 PALMOMR neur exam: palmomentals R, release sign
44 BULK neur exam: bulk
45 TONENECK neur exam: tone/neck
46 TONELIMB neur exam: rone limb
47 TREMORRE neur exam: tremor/rest

48* TREMORAC neur exam: tremor/action
49 MYOCLONM neur exam: diskinesia
50 BRAADFACE bradykinesia/face
51 BRADLIMB bradykinesia/limb
52 COLIMB coordination/limb
53 COTRUNK coordination/trunk
54 POSTURE posture/standing
55* GAIT gait, motor system
56* VIBRAT vibration, sensory system
57 ONSETAGE onset between ages 40 and 90
58 GLUCOSE lab: glucose
59 SODIUM lab: sodium
60 POTASSIU lab: potassium
61 BUN lab: BUN
62 CREATINI lab: creatinine
63 CALCIUM lab: calcium
64 ALKPHOSP lab: phosp.
65 TSH lab: TSH
66 B12 lab: B12
67 FOLATE lab: serum folate
68 VDRL lab: VDRL
69 PROTEIN lab: total protein
70 ALBUMIN lab: albumin
71 PHOSPHOR lab: inorganic phosphate
72 RBC lab: RBC folate
73 FABSTRUC impaired abstract thinking
74 FJUDGEME impaired judgement
75 FAPHASIA aphasia
76 FAPRAXIA apraxia
77 FAGNOSIA agnosia
78 ADL
79 IADL
80 HBP high blood pressure
81 HEART heart and circulation problems
82 STROKE stroke or effect of stroke
83 EYETROUB eye trouble
84 EARTROUB ear trouble
85 CHEST chest problems
86 BLADDER lose control of bladder
87 BOWELS lose control of bowels
88 DIABETES diabetes
89 KIDNEY kidney trouble
90 PARKINSO Parkinsonís disease
91 RELEASE release signs
92 SINCE years since onset
 

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My out the hat opinion here is that there probably exists no such thing as a "good diet" kinda like there exists no such thing as taking a good breath. Both food and breathing, while requirements, eventually kill us anyway. Less bad diets, and possobly less bad breathing techniques in less air pollution, may add a year or five, but we're dying anyway. Both good diet, bad diet and good breathing, bad breathing add to both intrinsic and extrinsic drivers of aging. Good drives less burden than bad, and in ways Watson may one day demystify.

Edited by Sthira

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Tetris? I've never played Tetris except when really stoned. Maybe you, too; hence your nice, out of box aging analogy? Also, maybe if more biogerontologists tripped ballz every now and then (think Steve Jobs) maybe there'd be more creative progress in field?

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While I agree that some damage accumulation from basic metabolism is inevitable, it seems to me that a good diet and engaging in exercise can not only reduce/eliminate additional damage, but actively work to reduce the amount of intrinsic damage that is occurring. I know you're skeptical of hormesis, but can't, for example, a good diet ramp up our bodies defenses and repair mechanisms by challenging it with mildly toxic compounds, i.e. xenohormesis? This diagram seems to suggest that plant phytochemicals like curcumin and ECGC can impact several of the aging-related pathways in the same ways as calorie restriction:

 

post-7043-0-77847800-1441567273.jpg

 

If this is correct, it (still) seems to me that diet (and extrapolating, exercise) are bona fide anti-aging interventions. They just are not as effective anti-aging interventions as CR because they don't cover as many of the multiple damage types, and/or don't reduce the damage as well as CR does. Thus the distinction is more a matter of degree, rather than kind. Is this right or am I still confused in this regard?

 

That shore is a purty document ya got there, Dean ;) . But having a nifty biochemical pathway chart — or even it plus the data underlying it — it doesn't in itself do anything to support your speculation here.

 

First, I very strongly suspect that if you actually tried to find the evidence (via the paper's references (what's your source, BTW?) or on your own initiatiive), you would find that nearly all of the biochemical effects imputed to the various phytochemicals, and especially curcumin, were done in vitro or at most in the GI tract and liver — ie, before they are metabolized, and not reflecting either physiologic local tissue levels of the compound or the actual final metabolite to which cells are actually exposed.

 

Second, the diagram purports to show that these phytochemicals have biochemical effects. This does not provide evidence that any of them actually reduce the amount of even one form of aging damage to a nontrivial degree in normal, aging animals (as opposed to after exposure to high levels of toxins or stressors, IOW, which is how these compounds or putative hormetic interventions are usually tested — ie, counteracting the aforementioned supernumerary sources of damage). And, indeed, I do not believe that any such evidence exists, although I'm inclined to entertain the possibility in the case of resveratrol.

 

Third, even if the case were slam-dunk that one or more of these phytochemicals were effective in reducing a subset of true, intrinsic aging damage (and again, AFAIK there is no evidence that they do so), you would also want to know something else: that under the dose and schedule administered, these compounds did not also inflict toxicity on the body equal to or greater than whatever benefit they might deliver. Since we don't have evidence of the former, however, we're not in a position to evaluate the latter.

 

Fourth, if the case were slam-dunk that one or more of these phytochemicals were effective in reducing a subset of true, intrinsic aging damage and they were nontoxic, that would prove that that one compound was an anti-aging compound: it would do nothing to support the contention that a good diet or exercise were also an anti-aging compound, any more than the fact that rapamycin actually is an anti-aging compound supports it.

 

And finally, while I take your point that it's hypothetically possible (though, again, AFAIK there is no evidence to support the contention) that one or more of these compounds might be a segmental anti-aging comound — one that did indeed reduce the rate of accumulation of one or more forms of aging damage but was "not as effective anti-aging interventions as CR because they don't cover as many of the multiple damage types, and/or don't reduce the damage as well as CR does" — I will none the less still emphasize that all of these compounds have been tested both for their effects on overall aging (in the form of lifespan studies in normal, otherwise-healthy aging mice or rats), both by the NIA's Interventions Testing Program (ITP) and, independently, by other competent labs. And in every single case, they have failed to do so.

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That shore is a purty document ya got there, Dean ;) . But having a nifty biochemical pathway chart — or even it plus the data underlying it — it doesn't in itself do anything to support your speculation here.

 

Thanks Michael - I wish I could take credit for the fancy diagram, and you are right, I should have included a reference. I apologize. It is figure 1 from [1]. Whether it supports my speculation, depends on what you think my speculation is, which I think you may have misunderstood - see below.

 

First, I very strongly suspect that if you actually tried to find the evidence (via the paper's references (what's your source, BTW?) or on your own initiative)

 

Uncharacteristically no  :)xyz , I actually didn't search for primary source evidence that the compounds in the diagram influenced the pathways as listed.  I don't understand all the biochemistry stuff anyway, and moreover I wasn't advocating that anyone should actually take any one of them, or the combination (more on that below).

 

... you would find that nearly all of the biochemical effects imputed to the various phytochemicals, and especially curcumin, were done in vitro or at most in the GI tract and liver — ie, before they are metabolized, and not reflecting either physiologic local tissue levels of the compound or the actual final metabolite to which cells are actually exposed.

 

As I said, I'm a "bear of very little brain" [3] when it comes to biochemistry. But as a result of your prompting, I have now looked at the evidence for one of the compounds (curcumin) and one of the pathways (mTOR). Here is the full text of a really good recent review [2] of curcumin's effects on mTOR signalling. You are definitely correct that it's hard to get physiologically-relevant levels of curcumin to where it needs to be in the body to have benefits. But [2] lists quite a number of phase I and II clinical trials using curcumin for cancer treatment, which appear quite promising, and which are definitely in vivo and not related to the GI or liver.

 

Moreover, I think you've somewhat misunderstood my intention with the post, and my reason for including that diagram.

 

What I was trying to show was that there is evidence that at least part of mechanism by which plant foods provide the health benefits they do is likely to be via modulation to some of the same pathways that are modulated by CR. My point wasn't to argue that these particular plant compounds are safe, effective or worth taking for their anti-aging or anti-cancer effects, as you seem to be railing against. Now I also think curcumin may have benefits for brain health, cardiovascular health, cancer [2], which you may be dismissing too quickly. But that wasn't the point of the post or that diagram...

 

Put another way, all I was suggesting was the point that you seem to confirm in the first part of your final paragraph, before you go off and bash these particular compounds some more in the rest of the paragraph.., namely:

 

 ... I take your point that it's hypothetically possible (though, again, AFAIK there is no evidence to support the contention) that one or more of these compounds might be a segmental anti-aging compound — one that did indeed reduce the rate of accumulation of one or more forms of aging damage but was "not as effective anti-aging interventions as CR because they don't cover as many of the multiple damage types, and/or don't reduce the damage as well as CR does" ...

 

Thank you - that was exactly the point, and the only point, I was trying to make. Compounds like curcumin, ECGC, and resveratrol may be crappy substitutes for CR, but not because CR works by some totally different mechanism than they do. Instead, all of them, including CR, may be tweaking the same set of biochemical pathways. It's just that CR is more effective as an anti-aging intervention (how much more effective in people remains to be seen...) because it tweaks many critical pathways simultaneously, and tweaks them in just the right way and to the right degree in order to appreciably reduce the accumulation of critical damage that constitutes aging, whereas these plant compounds do (or may) not.

 

In turn I think your response helps answer the core question that motivated this whole thread - namely the status of the concept of "intrinsic aging" in light of the current popularity of the "damage model of aging". Specifically, it seems that the idea of "intrinsic aging", which I previously understood (naively) to be independent of the damage associated with aging-related diseases and to be something which CR, and only CR, could magically slow, is an outdated concept. 

 

Instead, aging simply is the accumulation of various forms of damage. Therefore anything that can slow down the accumulation of these forms of damage can be considered an "anti-aging" therapy, although perhaps not an effective one in terms of actually extending lifespan due to limits on the degree and/or range of damage that it impacts. The same will be the case for example, when/if your SENS-sponsored research solves the problem of 7-ketocholesterol accumulating in arteries. It should be considered an anti-aging therapy by your and Aubrey's definition, despite the fact that it, by itself, may not have an appreciable impact on lifespan, except in particular narrow circumstances (e.g. animals or people destined to die early of heart disease).

 

In other words, the body gets damaged in so many ways, plant compounds like curcumin, or other focused interventions, don't appreciably impact lifespan because of their narrow and limited effects.

 

--Dean

 

-----------

[1] Cell. 2008 May 2;133(3):387-91. doi: 10.1016/j.cell.2008.04.019.

Xenohormesis: sensing the chemical cues of other species.

 

Howitz KT(1), Sinclair DA.

 

Author information:

(1)BIOMOL International, LP, 5120 Butler Pike, Plymouth Meeting, PA 19462, USA.

howitzkt@biomol.com

 

Free Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504011/

Many plant molecules interact with and modulate key regulators of mammalian

physiology in ways that are beneficial to health, but why? We propose that

heterotrophs (animals and fungi) are able to sense chemical cues synthesized by

plants and other autotrophs in response to stress. These cues provide advance

warning about deteriorating environmental conditions, allowing the heterotrophs

to prepare for adversity while conditions are still favorable.

 

PMCID: PMC2504011

PMID: 18455976

 

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

[2] Anticancer Agents Med Chem. 2013 Sep;13(7):988-94.

Hitting the golden TORget: curcumin's effects on mTOR signaling.

 

Beevers CS(1), Zhou H, Huang S.

 

Author information:

(1)Department of Pharmacology, Ross University School of Medicine, 630 US Hwy 1,

North Brunswick, NJ 08902, USA. cbeevers@rossmed.edu.dm

 

The polyphenol natural product curcumin possesses a plethora of biological and

pharmacological properties. For years, much interest has been placed in the

development and use of curcumin and its derivatives for the prevention and

treatment of cardiovascular, diabetic, and neurodegenerative diseases, as well as

cancer. Increasing evidence suggests that curcumin displays amazing molecular

versatility, and the number of its proposed cellular targets grows as the

research continues. The mammalian target of rapamycin (mTOR) is a master kinase,

regulating cell growth/proliferation, survival, and motility. Dysregulated mTOR

signaling occurs frequently in cancer, and targeting mTOR signaling is a

promising strategy for cancer therapy. Recent studies have identified mTOR as a

novel target of curcumin. Here we focus on reviewing current knowledge regarding

the effects of curcumin on mTOR signaling for better understanding the anticancer

mechanism of curcumin. The emerging studies of mTOR signaling and clinical

studies on curcumin with cancer patients are also discussed here.

 

PMCID: PMC3638063

PMID: 23272912

 

-------

[3] A.A. Milne - "When you are a Bear of Very Little Brain, and you Think of Things, you find sometimes that a Thing which seemed very Thingish inside you is quite different when it gets out into the open and has other people looking at it." - Winnie the Pooh

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First, I very strongly suspect that if you actually tried to find the evidence [that these compounds modulate these pathways] ... you would find that nearly all of the biochemical effects imputed to the various phytochemicals, and especially curcumin, were done in vitro or at most in the GI tract and liver — ie, before they are metabolized, and not reflecting either physiologic local tissue levels of the compound or the actual final metabolite to which cells are actually exposed.

I have now looked at the evidence for one of the compounds (curcumin) and one of the pathways (mTOR). Here is the full text

 

That illustrates my point: if you look at that review — and in particular, the section actually on curcumin and mTOR — you'll see that it's all been done in cancer cell lines in vitro.

 

But [2] lists quite a number of phase I and II clinical trials using curcumin for cancer treatment, which appear quite promising, and which are definitely in vivo and not related to the GI or liver.

Er... no, most of them are of the GI or liver: colorectal cancer, intestinal metaplasia of the stomach, pancreatic cancer, Bowen's disease, and oral leukoplakia. None of them IAC show clear biological effects, if for no other reason than the lack of a control group and the progression (rather than arrest or regression) of disease or precancerous lesions in the majority of each type of case. Eg., in their reference [6], there was histological improvement of the precancerous lesions in 2 of 7 patients with oral leukoplakia; aside from the fact that n=7 is not exactly a good statistical sample, we don't know that 2/7 control subjects would not have experienced the same thing. We don't know the outcome until they're done, and these trials won't prove the point anyway. Phase I trials are IAC just on bioavailability and lack of toxicity so severe as to prevent a real trial from even beginning. Phase II trials do usually attempt to gather early suggestions of benefit, tho' they aren't really reliable.

 

Moreover, I think you've somewhat misunderstood my intention with the post, and my reason for including that diagram.

 

What I was trying to show was that there is evidence that at least part of mechanism by which plant foods provide the health benefits they do is likely to be via modulation to some of the same pathways that are modulated by CR. My point wasn't to argue that these particular plant compounds are safe, effective or worth taking for their anti-aging or anti-cancer effects, as you seem to be railing against.

I was indeed railing against that in part — but even if (and again, no evidence yet presented ...) the mechanism by which these phytochemicals provide the health benefits they are purported to do is via modulation to some of the same pathways that are modulated by CR, that still doesn't address the central question, which is whether they affect the accumulation of intrinsic aging damage. CR does a lot of things: not all of them are related to any health benefits, and not all of those actually relate to it's effects on the aging process. CR lowers LDL cholesterol, for example, but (as discussed above) this isn't in itself the slowing of accumulation of aging damage, let alone its removal.

 

Put another way, all I was suggesting was the point that you seem to confirm in the first part of your final paragraph:

 

... I take your point that it's hypothetically possible (though, again, AFAIK there is no evidence to support the contention) that one or more of these compounds might be a segmental anti-aging compound — one that did indeed reduce the rate of accumulation of one or more forms of aging damage but was "not as effective anti-aging interventions as CR because they don't cover as many of the multiple damage types, and/or don't reduce the damage as well as CR does" ...

Thank you - that was exactly the point ... all of them, including CR, may be tweaking the same set of biochemical pathways. It's just that CR is more effective as an anti-aging intervention ... because it tweaks many critical pathways simultaneously, and tweaks them in just the right way and to the right degree in order to appreciably reduce the accumulation of critical damage that constitutes aging, whereas these plant compounds do (or may) not.

 

Again: I don't dispute the possibility of a segmental anti-aging intervention (as you point out, SENS is a segmental strategy, and I'm open to the likely possibility that pharmacological segmental anti-aging agents in the messing-with-metabolism heuristic of conventional biogerontology also exist). But again, (a) there's AFAIK no evidence that these compounds have such effects on even one form of aging damage, however many biochemical overlaps they may have with CR (and again, I don't think there's evidence that such biochemical overlaps exist on any meaningful in vivo way); and (b) even if there were, that wouldn't in itself support that healthy diet or exercise did so.

 

-----------

[1] Cell. 2008 May 2;133(3):387-91. doi: 10.1016/j.cell.2008.04.019.

Xenohormesis: sensing the chemical cues of other species.

Howitz KT(1), Sinclair DA.

Free Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504011/

PMCID: PMC2504011

PMID: 18455976

 

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

[2] Anticancer Agents Med Chem. 2013 Sep;13(7):988-94.

Hitting the golden TORget: curcumin's effects on mTOR signaling.

Beevers CS(1), Zhou H, Huang S.

PMCID: PMC3638063

PMID: 23272912

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Michael,

 

What is frustrating and frankly pretty discouraging for even an optimist like me is the fact that nothing seems to work anywhere near as well as CR to slow aging in other organisms, and it now appears unlikely based on the monkey CR studies that CR will have much of an effect on human aging. If its so hard, it seems pretty unlikely to me that the "pick 'em off one at a time" approach that SENS is pursuing will bear fruit within the foreseeable future in terms of a comprehensive set of therapies that actually move the ball when it comes to human longevity. You never responded to the question I posed in this post, so I'll pose it again:

 

Michael, here is something I've wondered about and perhaps you can answer. In the SENS engineering approach to defeating aging, the strategy is to target specific pathways by which aging-associated damage occurs, like the accumulation of intra- or extra-cellular gunk. Do you guys have a ballpark estimate of how many different specific gunk compounds there are that would each need to be targeted individually, like you are doing with 7-ketocholesterol, in order to conquer aging? Are there just a few, tens, hundreds or thousands that will need to be dealt with before we get a handle on postponing/curing the diseases of aging? It would seem to make a big difference wrt to the tractability, not to mention the timeframe, of the SENS approach.

 

Maybe telomerase therapy will be the ticket.  :)xyz

 

--Dean

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Yep. Frustrating and discouraging that nothing seems to slow aging. Even CR. But, at the same time, don't be stressed about their failures because stress, a message we get drilled into us 24/7, leads to increased aging. We can speed up aging, we're told, but we cannot slow it down. This is flawed.

 

Dean, it sounds like you're doing everything right in terms of "what they think they know" Wrt lifestyle and diet and that cold body suit thing you're doing (don't get pneumonia) to stay healthy until the magic wand twinkles anti aging fairy dust. But honestly, these academic and pharma scientists still haven't figured out how even aspirin works to cure a headache, or whether it's even safe to consume longterm. I don't think they'll EVER figure much of anything out -- beyond ER medicine -- until proper AI is developed and integrated. And those studies up there are mostly in (sick) mice anyway, which have little to do with our human aging prospects.

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...and it now appears unlikely based on the monkey CR studies that CR will have much of an effect on human aging.

 

If you're specifically talking about the 2012 NIH Nature study, I don't buy this.

MR compared the NIH and Wisc. Primate results here in this exhaustive blog post from 2013:

http://www.sens.org/research/research-blog/cr-nonhuman-primates-muddle-monkeys-men-and-mimetics

And related 2014 SENS video here:

 

...and then there are the Oki's ;)

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...and it now appears unlikely based on the monkey CR studies that CR will have much of an effect on human aging.

 

MR compared the NIH and Wisc. Primate results here in this exhaustive blog post from 2013:

http://www.sens.org/research/research-blog/cr-nonhuman-primates-muddle-monkeys-men-and-mimetics

 

Thanks Khurram. Perhaps you are right, I haven't emphasized enough the importance of Michael Rae's insightful, very thorough, massively detailedincredibly_creative, mega-review of the CR research on these forums previously. I'll try to remember to mention and link to it more diligently in the future  :)xyz.

 

Now the video from the SENS Conference you posted by the current lead researchers from the two monkey CR studies at Wisconsin and NIA are gems which I had not seen before. Thanks so much for posting them. First, I can't believe the conference organizers gave Ingram and Anderson only 15 minutes individually (two videos I've embedded below), and 20min together (the video Khurram posted above, included again below) to present and compare 25 years of data and results from what are arguably the two most important studies of anti-aging in the history of the field. Rozalyn complains at the beginning to an off-camera "Michael" about only getting 15 minutes for her talk. Michael, I hope that wasn't you...

 

Anyway - Khurram, I'm curious about your statement:

If you're specifically talking about the 2012 NIH Nature study, I don't buy this.

 

I am of course talking about that very paper/study [1]. I'm very curious to hear your optimistic interpretation of its results wrt CR and longevity. Having read the primary source, Michael's commentary on it, and watched these three videos, leads me to the conclusion presented in all those 'superlative' posts where I link to Michael's commentary, which can perhaps be summarized as I did here:

 

"The most parsimonious interpretation of the NIA monkey data (esp when coupled with the Wisconsin monkey data) is that once obesity is avoided, a healthy diet with (albeit only mild) calorie restriction is no better for primate longevity than the same diet without calorie restriction (or only enough CR to avoid obesity)."

 

Results from dogs (discussed here) and rodents (discussed here, here and here) seem to support this hypothesis as well - namely that staying slim via mild CR (at least up until old age) conveys health and longevity benefits, but more severe CR beyond that won't do very much to extend longevity - i.e. it might add a couple/few years, but probably not more. Aubrey argues why this is likely to be the case from an evolutionary perspective [2]. And contra your statement:

 

...and then there are the Oki's ;)

 

I've argued that the Okinawan longevity results, put in proper context, supports this "very modest longevity benefits of CR" thesis. In particular, this thread compares data from the Oki's and the 7th Day Adventists in order to argue that a good diet, healthy lifestyle, and avoiding getting fat (i.e. following the clean-living Adventists diet/lifestyle) will give you 10-14 more years on average than the typical, crap-eating, American couch potato. Restricting calories on top of that (like the Oki's of old did) doesn't seem to provide much (if any) additional benefit, although obviously cross-cultural comparisons are fraught with difficulties...

 

A couple weeks ago in this post, Michael seemed to even dashed the hope that we human CR folks might be different from the NIA monkeys by suggesting, contra to what I'd heard before, that the NIA CR monkeys did indeed show a reduction in IGF-1 (as we do), but no longevity benefits (like we're hoping for).

 

Michael, is Ingram mis-reporting his own groups data in the second video below @ 9:18 when he claims that neither GH nor IGF-1 were impacted by CR in the NIA monkeys? You'd think he'd know his own data, particularly since he was one of the authors of the much earlier (1995) study [3] you cited in your mega-review that appeared to show the opposite, namely that IGF-1 was reduced in the NIA CR monkeys. It seems to me the most likely explanation is that the early reduction in IGF-1 they reported in [3] disappeared over time, (re)raising the possibility that we might be a bit different from the CR monkeys, in a good way...  Of course, as you point out in the mega-review of the monkey studies, the Wisconsin monkeys did exhibit longevity benefits (albeit relative to obese, crap-eating controls), without a reduction in IGF-1, casting doubt on the notion that low IGF-1 is important for CR benefits...

 

But more generally Khurram, I'd like to hear your argument for an optimistic interpretation of the Wisconsin/NIA monkey CR trials (or the Okinawans vs. Adventists) - i.e that CR is likely to provide lifespan benefits significantly greater than is possible with a healthy diet & lifestyle which avoids overweight/obesity.

 

--Dean

 

 

Talk by Rozalyn Anderson on the Wisconsin CR monkey study results:

 

 

 

Talk by Don Ingram on the NIA CR monkey study results:

 

 

 

Talk by both Rozalyn and Don comparing and contrasting the two CR monkey studies (same as Khurram's link above, but to have all three in one place):

 

 

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

[1] Nature. 2012 Sep 13;489(7415):318-21. doi: 10.1038/nature11432.

Impact of caloric restriction on health and survival in rhesus monkeys from the

NIA study.

 

Mattison JA(1), Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL,

Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R.

 

Author information:

(1)Laboratory of Experimental Gerontology, National Institute on Aging, NIH

Animal Center, Dickerson, Maryland 20842, USA. mattisonj@mail.nih.gov

 

Comment in

Nature. 2012 Sep 13;489(7415):210-11.

 

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet,

is often reported as the most robust non-genetic mechanism to extend lifespan and

healthspan. CR is frequently used as a tool to understand mechanisms behind

ageing and age-associated diseases. In addition to and independently of

increasing lifespan, CR has been reported to delay or prevent the occurrence of

many chronic diseases in a variety of animals. Beneficial effects of CR on

outcomes such as immune function, motor coordination and resistance to sarcopenia

in rhesus monkeys have recently been reported. We report here that a CR regimen

implemented in young and older age rhesus monkeys at the National Institute on

Aging (NIA) has not improved survival outcomes. Our findings contrast with an

ongoing study at the Wisconsin National Primate Research Center (WNPRC), which

reported improved survival associated with 30% CR initiated in adult rhesus

monkeys (7–14 years) and a preliminary report with a small number of CR monkeys.

Over the years, both NIA and WNPRC have extensively documented beneficial health

effects of CR in these two apparently parallel studies. The implications of the

WNPRC findings were important as they extended CR findings beyond the laboratory

rodent and to a long-lived primate. Our study suggests a separation between

health effects, morbidity and mortality, and similar to what has been shown in

rodents, study design, husbandry and diet composition may strongly affect the

life-prolonging effect of CR in a long-lived nonhuman primate.

 

PMCID: PMC3832985

PMID: 22932268

 

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

[2] Gerontology. 2005 Mar-Apr;51(2):73-82.

 

The unfortunate influence of the weather on the rate of ageing: why human caloric

restriction or its emulation may only extend life expectancy by 2-3 years.

 

de Grey AD(1).

 

Author information:

(1)Department of Genetics, University of Cambridge, Cambridge, UK.

ag24@gen.cam.ac.uk

 

Much research interest, and recently even commercial interest, has been

predicated on the assumption that reasonably closely-related species--humans and

mice, for example--should, in principle, respond to ageing-retarding

interventions with an increase in maximum lifespan roughly proportional to their

control lifespan (that without the intervention). Here, it is argued that the

best-studied life-extending manipulations of mice are examples of a category that

is highly unlikely to follow this rule, and more likely to exhibit only a similar

absolute increase in maximum lifespan from one species to the next, independent

of the species' control lifespan. That category--reduction in dietary calories or

in the organism's ability to metabolize or sense them--is widely recognized to

extend lifespan as an evolutionary adaptation to transient starvation in the

wild, a situation which alters the organism's optimal partitioning of resources

between maintenance and reproduction. What has been generally overlooked is that

the extent of the evolutionary pressure to maintain adaptability to a given

duration of starvation varies with the frequency of that duration, something

which is--certainly for terrestrial animals and less directly for

others--determined principally by the weather. The pattern of starvation that the

weather imposes is suggested here to be of a sort that will tend to cause all

terrestrial animals, even those as far apart phylogenetically as nematodes and

mice, to possess the ability to live a similar maximum absolute (rather than

proportional) amount longer when food is short than when it is plentiful. This

generalization is strikingly in line with available data, leading (given the

increasing implausibility of further extending human mean but not maximum

lifespan in the industrialized world) to the biomedically and commercially

sobering conclusion that interventions which manipulate caloric intake or its

sensing are unlikely ever to confer more than 2 or 3 years' increase in human

mean or maximum lifespan at the most.

 

Copyright © 2005 S. Karger AG, Basel.

 

PMID: 15711074

 

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

[3] Neuroendocrinology Letters. 1995 17(3): 181-186

 

Effect of long-term dietary restriction on the somatotrophic axis in adult and aged monkeys

 
Cocchi, Daniela; Cattaneo, Lorena; Lane, Mark A.; Ingram, Donald K.; Cutler, Richard G.; Roth, George S., 1995: 
 
Previous studies showed that moderate dietary restriction has beneficial effects on the normal course of aging. The aim of the present study was to evaluate the ability of long-term diet restriction to modify the age-related reduction of somatotrophic function in monkeys. Plasma levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) progressively decreased with advancing age. Dietary restriction reduced plasma IGF-1 levels only in adult monkeys although a non-significant trend toward reduction was apparent in aged monkeys. Caloric restriction did not affect plasma GH levels in both age-groups. It appears, therefore, that long term dietary restriction can selectively affect IGF-1 levels.

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 I'm very curious to hear your optimistic interpretation of its results wrt CR and longevity.

 

I haven't researched the topic extensively. 

 

As unscientific as it seems, I rely on "gut feeling" and intuition. After over 15 years on the diet/List, I don't think this is an unreasonable or unscientific methodology. I don't, however, know about CR's impact on max. primate LS, but I'm guessing that too is extended, if not by much.

 

Bottom line:

 

...can it be as simple as this image from the home page of the Wisc. Primate Center?

calories.jpg

 

...or ...

 

cr_animals.jpg(above from my cron-web site home page)

 

... or the famous PBS/SciAm/Alan Alda segment from late 1999. The video clearly shows CR vs. non-CR in Wisc. primates.

 

I really think it is this simple -- "Calories, Calories, Calories" -- and if I overthought the issue, I'd be wasting my remaining LS ;)

 

I'll let MR have the last word...

Edited by KHashmi317

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Khurram,
 
You are clearly right in the case of the Wisconsin CR monkey results. Those monkeys did live longer than controls. It's just that at Wisconsin, the control monkeys ate crap (something I hesitate to say since you are literally eating what they did, although without all your extra vegetables) and ate it in ad lib amounts. As a result, they became obese, and looked like sh*t, as the photo you show above illustrates, developed diseases of aging and died relatively young.
 
No one is denying that CR provide health & longevity benefits relative to a standard American diet, which is pretty close to as bad as that of the Wisconsin control monkeys. The two more germane questions are:
  • How much extra health / longevity will CR provide relative to a crappy diet?
  • Will CR do any better that a healthy diet and lifestyle designed to avoid overweight/obesity?

For the first question, it appears to me the evidence from the Okinawans is 8-10 years on average, and evidence from the combination of Okinawans and Adventists, not to mention the animal data I mention above including most relevantly the NIA monkeys. suggests the answer to the second question is "probably not", or "not much better".

 

Of course I could be wrong, and I think it is this hope, along with the  fact that some of us value the other benefits of CR very highly, that keep us doing it, or in my case, something resembling it.

 

--Dean

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Since Michael hasn't responded to my (re)asked question in this post about approximately how many intra- and extracellular 'gunk' compounds exist and will need to be tackled for SENS therapy to be effective, I figured I'd try to go straight to the horse's mouth, and ask Aubrey (via Quora.com) about it. Aubrey is quite active on Quora, and responded within a couple hours. Thanks Aubrey! (although I highly doubt he'll see this). Here is my question and his response:

 

Q: How many different forms of intra- and extracellular 'gunk' will need to be cleaned up for the SENS anti-aging approach to work?
 
Question Details: SENS research is making progress on eliminating some forms of gunk that contribute to aging, e.g. 7-ketocholesterol for CVD. But the viability and timetable of the SENS strategy depends on how many such compounds will need to be cleaned up. So does Aubrey think it's closer to 10, 100 or 1000?
 
Aubrey de Grey: Great question. We don't really know, of course. At present our focus is on just three of each (intra and extra), but transthyretin's role in the extreme elderly has only been known for a few years, and I would be quite surprised if new examples don't turn up pretty soon. The good news, though, is of course that the same methodology should lead to the therapies for each case, such that we can take advantage of what we learned for the first examples to speed up the pipeline for later ones. So actually, and especially when we factor in the longevity escape velocity dimension, the viability and timetable of the SENS strategy doesn't depend too badly on how many such compounds will need to be cleaned up.
 
I appreciate him answering so quickly, but I found his response to be a little disappointing. Sure there might be some leverage gained from the first solution that speeds up subsequent ones. But I'm not convinced there will be that much leverage to be gained. I added this comment to Aubrey's answer:
 
Thanks Aubrey!
 
But as you've said elsewhere on Quora (here: What is the most low-hanging fruit in aging research?) cleaning up each one of these gunk compounds is likely to do very little to extend lifespan. In fact, you said significant life extension will require tackling not just intra- and extracellular gunk, but having "reasonable effective solutions" to all seven major causes of aging.
 
If there are more than 10-20 (to say nothing of hundreds or thousands...) gunk compounds that need to be addressed, it would seem like it's going to be a very long time before escape velocity will be achieved.

 

We'll see if he responses...

 

--Dean

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I appreciate him answering so quickly, but I found his response to be a little disappointing. Sure there might be some leverage gained from the first solution that speeds up subsequent ones. But I'm not convinced there will be that much leverage to be gained.

It could be the case that maybe just some <100% and not all of (mousy cancerous) gunk (senescent cells) needs removal?

 

In this mouse study AP20187 removed just 60-70% of senescent cells and yet seems to have delayed tumor formations and organ deterioration. Their cute mousy little median lifespans were then extended by 17 to 35 percent.

 

Study:

 

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 2016; DOI: 10.1038/nature16932

 

They'll need billions of dollars and ten more decades of conservative hand-wringing to figure out if it's relevant, though.

Edited by Sthira

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Sometime later...

 

Aubrey did respond! Here it is:

 

That doesn't follow [that escape velocity may be a long way off], no. Yes we need to fix all seven reasonably well, which is why SRF mainly prioritises the hardest ones. But the nature of LEV is that we buy enough time by fixing the most severe examples within each category, to figure out how to fix the next set, etc. I currently see no reason to revise the timeframes for getting to LEV that I've been giving for over a decade, other than of course with regard to the impact that has been due to lack of funding.

 

I'm still pretty dubious... It seems that if we've learned anything about aging, it is that it's extremely multifaceted, which isn't surprising given how incredibly complicated human metabolism is. So it is going to require solving lots of different problems, and subproblems, and sub-subproblems, all of which serve as impediments (i.e. gating functions) to significant lifespan extension. Not addressing head-on how many forms of damage will need to be cleaned up seems to be a good way to engender optimism (i.e. "all we need to do is solved 7-ketocholesterol and a couple others to achieve escape velocity...") , but perhaps not so good science, or more accurately, not so good engineering.

 

Aubrey & Co. wants to turn solving aging into an engineering problem. Engineering involves breaking a problem down into a series of steps and then figuring out how to tackle each one. They seem to have done a pretty good job at the first level decomposition, by identifying the 7 major causes of age-related damage. But until/unless SENS goes a level deeper, and looks in more detail at just what it will take to develop "reasonably effective solutions" to each of the 7 major causes, it seems hard to take seriously Aubrey's optimistic estimates for the time to reach longevity escape velocity (i.e. a couple decades with adequate funding)...

 

--Dean

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^^^ Dean, I doubt de Grey would disagree with much of what you've written: aging is hard to solve, metabolism is complicated, funding is short, time is passing... And since he's a computer scientist I'm sure the idea that artificial intelligence must play a role in solving aging riddles isn't lost. Too bad more partnerships with startup AI orgs isn't happening. Or is it?

 

I'm curious about their (SRF) tactics, though. Why prioritize hardest problems first? In your own life, solving your own problems, don't you try to solve the easiest problems first? Then go on up and attempt the next harder sets from victory? At this point, I'm sure any solution to any problem would be great for SENS. I wish they were a little more creative, though. Solve the easiest problems with the highest demand first, maybe?

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I will address all (OK, most) of this, including several points of confusion in Dean's followup question — but I'm busy as the Devil himself, and you'll have to give me at least a few days.

 

Telomerase "therapy" in humans is likely is the ticket to cancer, BTW, and certainly not long and healthy life.

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Good point Sthira about prioritization. In my life I too like to achieve "minor victories" that embolden me to take on the major challenges.  It would seem this could be especially useful for SRF (the SENS Research Foundation), since a quick success could create a snowball effect wrt funding.

 

I'm not even sure how Aubrey can coherently claim to be to "mainly prioritizing the hardest [causes of aging]" when they've only done a relatively shallow characterization of the various causes of aging to begin with. For example, without knowing how many different forms of intracellular or extracellular 'gunk' exist, and how diverse they are, how can he know whether mopping them up will make these two among the hardest, or among the easiest of the seven causes of aging to conquer?

 

--Dean

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I will address all (OK, most) of this, including several points of confusion in Dean's followup question — but I'm busy as the Devil himself, and you'll have to give me at least a few days.

 

Great Michael! I'm looking forward to it. I understand you've got more important things to do than settle our squabbles - like helping to actually solve the problems we're squabbling about...  :)xyz

 

Telomerase "therapy" in humans is likely is the ticket to cancer, BTW, and certainly not long and healthy life.

 

I tend to agree with you, and I hope you recognize I was being sarcastic when suggesting telomerase activation may be the "ticket" to immortality.

 

--Dean

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