Should We Mirror the Long-Lived to Live Long?

[Dean Pomerleau]

All,

 

Over on the Body-mass index and all-cause mortality thread, TomB posted the following, asking about what we might learn from the lifestyle and biomarkers of the very old in order to optimize our own diets and lifestyles.

 

TomB said (my emphasis):

 

But what about the very old? Dean pointed to the "optimal late-life BMI for longevity" thread where the BMI distributions compiled by Michael Lustgarten seem to be, quote: "19.3-24.4 kg/m2, with an average BMI of 21.8" - not exactly even in overweight category, FWIW, even allowing for any BMIs creeping upward with age.

...

But is there any evidence at all that the very old have a diet that in any way differs from SAD except in quantity? I'd be interested in studies such as PMID:25446984:

 

Metals in plasma of nonagenarians and centenarians living in a key area of longevity.

 

Abstract

The concentration of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn) and selenium (Se) in plasma of 76 nonagenarians (mean age, 89.0±6.3 years), 64 centenarians (mean age, 101±1 years) and 24 middle-aged subjects as controls (mean age 61.2±1.1 years), was determined by sector field inductively coupled plasma mass spectrometry. All the subjects lived in Sardinia, an Italian island, that has the higher prevalence of centenarians than in other European countries. A comparison among the three classes of age showed a significant depletion of Ca, Co, Fe, Mn and Se (all p<0.001) in nonagenarians and centenarians with respect to controls. In particular, the geometric mean (GM) values of Ca, Co, Fe, Mn and Se were: 94.1 μg/ml, 0.46 ng/ml, 1314 ng/ml, 2.47 ng/ml and 111 ng/ml in controls; 87.6 μg/ml, 0.22 ng/ml, 815 ng/ml, 1.07 ng/ml and 88.9 ng/ml in nonagenarians; 87.0 μg/ml, 0.29 ng/ml, 713 ng/ml, 1.27 ng/ml and 81.9 ng/ml in centenarians. The highest inverse relationship with age was observed for Fe (p<0.001; ρ=-0.352) and Se (p<0.001; ρ=-0.417). This trend was also observed when data were sorted by gender. On the other hand, Cu and Mg levels in plasma remained substantially unchanged during aging. As regards Cu, it was significantly higher in females than in males in controls (GM, 1294 ng/ml vs. 1077 ng/ml; p=0.012), in nonagenarians (GM, 1216 ng/ml vs. 1081 ng/ml; p=0.011) as well as in centenarians (GM, 1226 ng/ml vs. 1152 ng/ml; p=0.045) and in hypertensive subjects with respect to healthy people (GM, 1215 ng/ml vs. 1129 ng/ml; p=0.021). These data can be used to enhance knowledge and support the research on: i) metals involved in aging in areas with high rates of human longevity; ii) variables (gender, lifestyle habits and health status) as critical determinants in aging; and iii) mineral intake and supplementation at older age affecting the healthy aging.

 

What's interesting to me in this study, is that the subjects were all from the same area, which cuts down on the number of confounders wrt. ethnic background, cultural factors etc. I don't know how many far-going conclusions one can derive from this, but this is the direction I think is fruitful for exploration.

 

[Note: the blue highlights above will factor into the discussions below]

 

That other Michael (i.e. Mike Lustgarten hereafter referred to as 'Mike' to avoid confusion) and I have had several debates on this subject before on the CR Facebook forum.

 

Namely, Mike likes to look at the characteristics (e.g. BMI, or selenium level) of very long-lived people (i.e. who've made it into their 90s or 100s), declare "they must be doing something right!" and target those same biomarker levels, diet characteristics and/or lifestyle practices for himself, and advocate others do the same to maximize their chance of living a long time.

 

But as I've tried to point out to him on several occasions (relatively unsuccessfully it would seem), this approach to diet and lifestyle optimization is naive and fraught with problems. Here are the reasons why.

 

It all boils down to one overarching observation - we're not like very old people. But just how we are unlike them, and why it matters, will take some unpacking.

 

Freakishly good gene combinations - Perhaps the most common way for people these days to reach a very ripe old age is to have freakishly good genes. This allows them to avoid the major killers, like heart disease and cancer, often despite bad diet and lifestyle habits. Think of this as the George Burns effect. Actor George Burns lived to 100 despite smoking 10-15 cigars per day for 70 years (ref). Don't try that at home sports fans! The same thing is happening when you hear on TV about the latest 110 year old who attributes their longevity to "eating two strips of bacon per day" or "drinking whisky".

 

In short, just because someone with freakishly good genes got away with a bad habit and lived to a ripe old age, doesn't mean you could, or should, try to emulate them, since most of us have crappy, run-of-the-mill gene combos, by definition, which means emulating such behavior would kill us quick.

 

Survivor bias - In addition to a few folks with freakishly good genes, in any large population, there will also be a few folks with average genes who get lucky, and live to a ripe old age, avoiding the major killers. In fact, they might have bad genes or lifestyle habits that would on average shorten lifespan, but because they got lucky, they lived a long time.

 

Here are a couple great examples of survivor bias (and/or other explanations discussed below) from the study Tom posted above (PMID:25446984), and that I've highlighted in blue. Notice above in that study the people who lived a very long time, into their 90s and 100s, had significantly lower levels of calcium and iron than did middle-aged controls. What gives? Isn't calcium supposed to be good for bones and iron important for avoiding anemia-complications and having a healthy immune system? Those benefits of Ca and Fe may hold true for middle-aged folks, and even the average senior. But at the same time, calcium can calcify arteries, and iron can cause oxidative damage, both of which can exacerbate the major killers - heart disease and cancer.

 

So if you are one of those very rare individuals with either good genes and/or very good luck, you can get away with keeping Ca and Fe on the low (deficient) side, and avoid Ca and Fe deficiency-related maladies that would kill off the average person early - like a hip fracture from weak bones or a respiratory infection from a weak immune system. If you get lucky and escape those downsides of low Ca and Fe, then you are golden because keeping them low will help you avoid heart disease and cancer and hence live a long time. But if you're like the average person, low Ca and/or Fe will lead to broken bones and/or infections that will cut your life short on average. In other words, low Ca and/or low Fe will harm most people, and only benefit a lucky few.

 

Another good example here is directly related to immunity - namely white blood cell (WBC) count. Several studies (discussed in http://dx.doi.org/10.1371/journal.pone.0127550) have found that that oldest of the old have  low WBC. This is great for them, since it enabled them to avoid the major diseases of aging, which are triggered by inflammation. But they very well may have gotten luck or had good genes, enabling them to avoid infections that would normally have killed an average person with such a low WBC.

 

In short, it doesn't necessarily pay for the average person to try to emulate the blood chemistry profile of the very old.

 

Late Life / Near Death Changes - It's not just good genes or survivor bias (i.e. freakish luck) that sets the oldest of the old apart from the rest of us, and which makes them poor models to emulate. Why? Because biomarkers change drastically later in life, and especially when you are approaching death, which centenarians almost invariably are. So their blood chemistry levels when they are old aren't necessarily reflective of what got them to a ripe old age.

 

Serum cholesterol is a great example of this. For various reasons, ranging from intestinal parasites to cancer, serum cholesterol tends to drop precipitously as people get sick and approach death. This can result in several misleading observations. First, old people with the highest cholesterol often live longer (i.e. have a lower mortality rate) than old people with low cholesterol, due to reverse causality. That is, the folks with low cholesterol are low because they've got a disease that will soon kill them. This observation (i.e. mortality risk is lowest in elderly folks with high cholesterol) is often pointed to by saturated fat apologists who like to claim keeping cholesterol from getting too low is critical for health and that low cholesterol is as bad or worse than high cholesterol. Bogus argument.

 

Conversely, the oldest of the old, e.g. centenarians or supercentenarians, who are almost invariably within a year or two of death, may exhibit freakishly low cholesterol, for the same "reverse causality" reason - i.e. they are close to death causing low cholesterol.

 

In both cases, the cholesterol level these old or freakishly old folks exhibit when they get to their ripe old age tells us nothing about what cholesterol level is best to get you to old age. For that we can look at longitudinal studies, that show low cholesterol in middle age is associated with improved longevity, for obvious reasons.

 

That's why, BTW, studies of the freakishly old often look at their offspring or (younger) siblings as well, to see what characteristics people with similar genes had when they were younger, to avoid these late life changes/biases.

 

In summary, looking at the blood chemistry, diet and/or lifestyle of very old people and trying to emulate them is fraught with difficulty, and therefore ill-advised. This is unfortunate, since it makes us much more reliant on longitudinal studies in people and intervention studies in animals, which have their own pitfalls, as we are all well-aware.

 

--Dean

[Dean Pomerleau]

All,

 

Here is discussion by the author of a new study [1] that lends support to the idea above that we shouldn't try to imitate the oldest of the old in order to live long ourselves.

 

They looked at very long-lived people (90s and 100s) from several studies and compared the onset of major killers like cancer, CVD and diabetes. They found that the longest lived folks weren't languishing with debilitating diseases for a very long time, as some people fear. Instead, they found:

 

The age at which 20% of each of the groups with exceptional longevity experienced specific

diseases was between 18 and 24 years later than in the reference groups, stratified according

to sex.

 

So that's nice. But unfortunately, the authors point out that it appears to be genes, rather than clean living, that got people to such a ripe old age without disease or disabilities:

 

"A lot of concern is that, well, if you live a long time, you're just going to be bedridden. And what they're showing is that's not true. The people who are living longer are living healthier," said Dr. Anne Newman, director of the Center for Aging and Population Health at the University of Pittsburgh.

 

"Their health span was longer, and that's the important piece of it," added Newman, a professor and chair of population health sciences and epidemiology.

 

So what's their secret?

 

According to Milman [author of [1]], "Genetic factors are thought to be the main reason. We have identified several genetic factors that appear to slow aging and/or protect from diseases."

 

Environment factors—at least among these long-lived people—seem to be less important, she noted.

 

"Our centenarians were not practicing particularly healthy behaviors: 60 percent of men and 30 percent of women were smokers, less than half exercised regularly, and approximately 50 percent were overweight or obese," Milman noted.

 

So the people who enjoy the best longevity don't generally do it through clean living, unfortunately, so it doesn't appear that we can learn very much directly from them about how to get there ourselves, except perhaps to pick better parents next time around...

 

--Dean

 

-----------

[1] J Am Geriatr Soc. 2016 Jul 5. doi: 10.1111/jgs.14222. [Epub ahead of print]

 

Compression of Morbidity Is Observed Across Cohorts with Exceptional Longevity.

 

Ismail K(1,)(2), Nussbaum L(3), Sebastiani P(3), Andersen S(4), Perls T(4),

Barzilai N(1,)(2), Milman S(1,)(2).

 

Author information: 

(1)Division of Endocrinology, Department of Medicine, Albert Einstein College of 

Medicine, Bronx, New York. (2)Institute for Aging Research, Department of

Medicine, Albert Einstein College of Medicine, Bronx, New York. (3)Department of 

Biostatistics, School of Public Health, Boston University, Boston, Massachusetts.

(4)Geriatrics Section, Department of Medicine, School of Medicine, Boston

University and Boston Medical Center, Boston, Massachusetts.

 

OBJECTIVES: To determine, in a sample of Ashkenazi Jewish aged 95 and older,

whether there is a compression of morbidity similar to what has been reported in 

other cohorts with exceptional longevity.

DESIGN: Case-control study.

SETTING: Longevity Genes Project (LGP) and New England Centenarian Study (NECS).

PARTICIPANTS: LGP (n = 439, mean age 97.8 ± 2.8) and NECS (n = 1,498, mean age

101.4 ± 4.0) participants with exceptional longevity and their respective younger

referent cohorts (LGP, n = 696; NECS, n = 302).

MEASUREMENTS: Self- and proxy reports of age of onset of cancer, cardiovascular

disease, diabetes mellitus, hypertension, osteoporosis, and stroke.

RESULTS: Long-lived individuals from LGP and NECS had later age of onset of

cancer, cardiovascular disease, diabetes mellitus, hypertension, and osteoporosis

than their respective younger reference groups. The risk of overall morbidity was

lower in participants with exceptional longevity than in younger participants

(NECS men: relative risk (RR) = 0.12, women: RR = 0.20; LGP men: RR = 0.18,

women: RR = 0.24). The age at which 20% of each of the groups with exceptional

longevity experienced specific diseases was between 18 and 24 years later than in

the reference groups, stratified according to sex.

CONCLUSION: The similar extension of health span and compression of morbidity

seen in NECS and LGP participants with exceptional longevity further validates

the utility of these rare individuals for the study of factors that delay or

prevent a broad spectrum of diseases otherwise associated with mortality and

disability.

 

© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics

Society.

 

DOI: 10.1111/jgs.14222 

PMID: 27377170

[Dean Pomerleau]

All,

 

The previous study I cited showed mimicking long-lived old folk's lifestyle wasn't such a good idea due to the "George Burns Effect". But what evidence is there that their biomarkers aren't the right way to go? After all, perhaps it was their genes that got them there, but there has got to be something about their biochemical milieu that is longevity-promoting right?

 

Maybe, but by the time they get old, their blood chemistry and other biomarkers don't have much to teach us either, as this new study [1] points out. It followed 26,000 people older than 80 with Type 2 diabetes in the UK to see how several important biomarkers correlated with mortality. 

 

They found the lowest mortality among people whose HBA1c was between 7.0-7.4, whose blood pressure was around 155/95, and whose total cholesterol was over 212 mg/dL. Values below that for all three metrics were associated with increased mortality. And these folks were diabetics so if anything you'd expect these seemingly elevated values to be detrimental. But apparently not.

 

Obviously all of these values would be far too high for younger folks like most of us to target. Once again we see that mimicking the profile that minimizes mortality in older folks is not a good way for younger folks to ensure healthy aging.

 

--Dean

 

--------

[1] J Am Geriatr Soc. 2016 Jul;64(7):1425-31. doi: 10.1111/jgs.14215. Epub 2016 Jun
13.

Mortality in Individuals Aged 80 and Older with Type 2 Diabetes Mellitus in
Relation to Glycosylated Hemoglobin, Blood Pressure, and Total Cholesterol.

Hamada S(1), Gulliford MC(1,)(2).
 

Free full text: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/jgs.14215

OBJECTIVES: To evaluate whether low glycosylated hemoglobin (HbA1c), blood
pressure (BP), and total cholesterol (TC) are associated with lower risk of
all-cause mortality in very old individuals with type 2 diabetes mellitus.
DESIGN: Population-based cohort study.
SETTING: Primary care database in the United Kingdom.
PARTICIPANTS: Individuals aged 80 and older with type 2 diabetes mellitus (N =
25,966).
MEASUREMENTS: Associations between baseline HbA1c, BP, and TC and all-cause
mortality were evaluated in Cox proportional hazards models. Analyses were
adjusted for sex, age, duration of diabetes mellitus, lifestyle variables, HbA1c,
BP, TC, comorbidities, prescribing of antidiabetic and cardiovascular drugs, and
participants' general practice.
RESULTS: There were 4,490 deaths during follow-up (median 2.0 years; mortality
104.7 per 1,000 person-years). Mortality in participants with low (<6.0% (<42
mmol/mol)) or high (≥8.5% (≥69 mmol/mol)) HbA1c was similar to that in those with
the reference HbA1c (8.0-8.4% (64-68 mmol/mol)). Mortality was lowest in
individuals with HbA1c of 7.0-7.4% (53-57 mmol/mol) (80.9 per 1,000 person-years,
adjusted hazard ratio (aHR) = 0.80, 95% confidence interval (CI) = 0.70-0.91, P =
.001). Mortality was higher in individuals with lower BP (e.g., <130/70 mmHg,
151.7 per 1,000 person-years, aHR = 1.52, 95% CI = 1.34-1.72, P < .001 vs
reference BP <150/90 mmHg) and in the lowest TC category (<3.0 mmol/L, 138.7 per
1,000 person-years, aHR = 1.42, 95% CI = 1.24-1.64, P < .001 vs reference TC
4.5-4.9 mmol/L). The relationship between TC and mortality varied according to
sex and prescription of lipid-lowering drugs.
CONCLUSION: Low HbA1c, BP, and TC may be associated with higher mortality in very
old adults with type 2 diabetes mellitus. Further research is required to
understand these associations and to identify optimal treatment targets in this
population.

© 2016 The Authors. The Journal of the American Geriatrics Society published by
Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.

DOI: 10.1111/jgs.14215
PMID: 27295278

[AlPater]

Dean, re:

Compression of Morbidity Is Observed Across Cohorts with Exceptional Longevity.
Ismail K, Nussbaum L, Sebastiani P, Andersen S, Perls T, Barzilai N, Milman S.
J Am Geriatr Soc. 2016 Jul 5. doi: 10.1111/jgs.14222. [Epub ahead of print]
PMID: 27377170
http://sci-hub.cc/10.1111/jgs.14222

``The LGP study previously demonstrated that its par-
ticipants with exceptional longevity did not have healthier
habits throughout their lives than contemporaries, suggest-
ing that environment was not an important differentiating
factor for these individuals’ enhanced life and health
spans.25``

Although this was said above, in their reference [25], controls had much fewer obese folks especially for men, and the longer-lived men also smoke >100 smokes significantly more.  Also, as shown below, the long-lived folks were more educated than the man on the street at the time.  This did not seem to play in analyses.  Case-control experiments are in my opinion soft science although long-lived folks are older and so they do have something going for them to get there.

25. Lifestyle factors of people with exceptional longevity.
Rajpathak SN, Liu Y, Ben-David O, Reddy S, Atzmon G, Crandall J, Barzilai N.
J Am Geriatr Soc. 2011 Aug;59(8):1509-12. doi: 10.1111/j.1532-5415.2011.03498.x. Epub 2011 Aug 3.
PMID: 21812767
http://sci-hub.cc/10.1111/j.1532-5415.2011.03498.x

"The study population had a mean age of 97.3=/-
2.8 (range 95–109) and included 74.6% women. In
general, this study population is well educated for the per-
tinent time period, with almost 75% of the individuals
completing at least high school."

[Dean Pomerleau]

Thanks Al!

 

Yes you're right, it appears from your reference [25] that fewer centenarian men (but not women) smoked during their lifetime as compared to the (younger) NHANES cohort.

 

Fewer centenarians were obese, but when the overweight and obese categories were combined, there wasn't a significant difference between the percent of heavy long-lived folks vs. the percent of heavy younger folks. The mean reported peak lifetime BMI was also not different between the two cohorts (both around 25).

 

Nor was their a significant difference in the percentage of people who reported following low-calorie, low-fat or low-salt diets in the two cohorts. The long-lived men were less likely to report engaging in moderate physical activity than the NHANES men.

 

Case-control experiments are in my opinion soft science although long-lived folks are older and so they do have something going for them to get there.

 

Agreed, but it looks pretty strongly like it's their genes (or perhaps luck) that got them there, and not their diet or lifestyle.

 

--Dean

[TomBAvoider]

Aargh, so annoying, I lost another post. I really should quit writing directly in the browser window - too many lost posts :(

 

Moving on:

 

So the people who enjoy the best longevity don't generally do it through clean living, unfortunately, so it doesn't appear that we can learn very much directly from them about how to get there ourselves, except perhaps to pick better parents next time around...

 

I think you’ve made a convincing case that we - at late middle age in particular - but at any age in general, should not model our health behaviors on the very old cohort.

 

And I used to joke for a long time that the 5 most important factors in successful aging are (1) genes (2) genes (3) genes (4) genes (5) luck, with “luck” being things like not getting hit by a truck, but also not being exposed to deleterious stuff through sheer dumb luck rather than healthy behaviors (like the recent CMV revelations). But I still hoped that healthy behaviors might come in somewhere at maybe (107) in impact.

 

Joking aside, there is this idea that healthy living allows you to live to your genetic potential, whereas unhealthy living does not. I remember MR making this argument specifically in the case of Calment - OK, she lived to 122, but CRON might have pushed her to her 130 full potential. Instead, she smoked etc. 

 

But is that hypothesis correct? Intuitively it makes a lot of sense. Do the numbers bear it out? Is it really true that the oldsters in that study would have added another 2-5-10 years to their lifespans had they in fact engaged in “clean living” as you put it?

 

I rather think the numbers don’t bear that out. I rather think the evidence tends to show, that short of extreme behaviors such as morbid obesity, alcoholism etc., you live about as long with super-health-nut behaviors as with average-Joe. It’s like the case with the two LaLanne brothers. Jack LaLanne lived to 96, and he was a health nut - maybe not to our standards, but by standards of what common wisdom advice would prescribe - healthy diet, exercise, clean living. His brother did none of that - although never abused himself - and lived to 97. Now, Jack died from the flu - but you gotta die from something, and his healthy lifestyle apparently did not give him strong enough immune system to battle a common bug. Although it’s possible that with super health nut behaviors you die in better shape than the slothful average, but at about the same age - maybe you are functional longer.

 

Here’s my thought process. If indeed the healthiest living folks survived longer, then you would expect that at the very edge of the bell curve, the very oldest old cohort, you would be left *only* with the healthiest living oldsters, their less healthy living cohorts not having reached their genetic potential.

 

And that manifestly is not the case - in point of fact Calment herself is proof of that. Or the other example I gave for the currently longest living MALE, at over 112 age, a survivor of both the Jewish Ghetto and a concentration camp - I need not tell you that it’s doubtful that his diet was particularly healthy for years and years at a stretch. Yet, there they are.

 

In fact, one could do something as simple as make supercentenarian status the cutoff - that for the reason that it’s very rare to achieve supercentenarian status at all. And we have no evidence that the over 110 year olds have had healthier life-long habits than the cohort who died between 100 and 109. 

 

So what of those countless studies showing how this behavior or that results in better/worse all cause mortality? Maybe that’s where genes and luck enter - some people are able to handle the unhealthy (within limits) behaviors while others with worse genes and/or luck succumb.

 

But isn’t this just an argument for the position that Dean holds: it really doesn’t matter (for health-life span) what you do as long as you take ordinary care and stay within low-mid 20’s BMI. This would imply that our health-nut struggles - such as richly illustrated on this site - are meaningless doodles on the margins. May as well spare ourselves the effort - unless we’re doing it out of pure intellectual curiosity - it won’t affect the outcome much if at all.

 

Even if we grant the preceding, it then also implies something else: only extremely radical measures might have a chance to overcome the limitations of the genetic profile. Extreme CR - was one attempt - and a mistaken one, according to Dean. Maybe SENS to the rescue (I doubt it). Or something else?

 

In other words - go BIG, or go home. Following Michael Pollan is not "going big". We need something radical.

[Dean Pomerleau]

Tom,

 

I agree with you that a healthy diet and lifestyle (to say nothing of serious CR) are not going to help us achieve extreme longevity (100+) - to get their given the medical technology available today requires freakishly good genes or good luck. Diet and lifestyle don't seem to play much of a role.

 

But I still point to the longevity advantage enjoyed by the 7th Day Adventist as evidence that "clean living" (without necessarily any sort of CR) will indeed help the average person to beat the average longevity by a substantial amount, allowing people who'd normally croak in their mid to late 70s to make it to 85-90 in reasonably good shape. That seems like a pretty big win, particularly when many of us could be on the cusp of SENS technology that could dramatically amplify small healthspan/lifespan differences over the coming few decades.

 

--Dean

[Mechanism]

Edited