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Puzzling Role Of Genetic Risk Factors In Human Longevity

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Thanks to Sibirak for posting this paper in the CR Science & Theory section in the thread "Associations of Body Mass Index and Waist Circumference with 3-Year All-Cause Mortality Among the Oldest Old" on 06/04/2018. I thought it was a consequential enough paper that it deserved its own thread, and I hereby re-post it for discussion and general edification. Some reasons why this paper is important:


1)Many of us are fans of sites like 23andme where we can browse our genetics for variants that might be informative from a health perspective. This paper makes it clear that just having our gene variants identified is of limited usefulness, because a "detrimental", or "protective" variant is so only conditionally, and it can reverse impact upon a variety of factors including age and interaction with other genes as well as the environment, lifestyle factors and medication.


2)Any number of studies showing benefits/harm of a diet, lifestyle choice or medication is highly dependent on your individual mix of genes, age and environment. What might be good advice for one person may be irrelevant or harmful to another


3)It makes clear that the current state of knowledge about how all these factors interact make a lot of dietary advice and interventions, basically random.


4)Your individual background is a key factor in your health and longevity


Puzzling role of genetic risk factors in human longevity: “risk alleles” as pro-longevity variants


Biogerontology. 2016; 17: 109–127.
Published online 2015 Aug 26. doi:  10.1007/s10522-015-9600-1
PMCID: PMC4724477
PMID: 26306600



Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from “bad” to “good”); (iii) gene–gene interaction; and (iv) gene–environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease “risk allele” can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

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I agree about pointing out the large inter-individual differences. 


But at this point we may fold up shop and quit writing here. No use.


My reasoned thought though is that there still is a significant part of general rules which are, as a whole, applicable to everyone. Such as: better to avoid junk food, better to avoid an excess of animal protein, better to avoid an excess of carbs and simple sugars. Within these general rules we may apply the individual exceptions, like if we are more or less tolerant to dietary cholesterol, simple sugars, phytotoxins and so on.


For example the xenohormetic diet is great for many of us, but some people are intolerant to the same phytotoxins which vause the beneficial hormetic reactions.

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better to avoid an excess of animal protein


My muscle wasting disease, SBMA, attributed to a single gene polymorphism is found clinically to produce low GH/IGF1 levels and statistically significant lowered risk of cancer.  Exogenous GH injections in the short term improve muscle mass and function but accelerates development of insulin resistance/metabolic syndrome correlated to faster disease progression and is likely detrimental long term.  After a fair amount of dietary experimentation I'm finding Protiein Sparing Modified Fasting, https://en.wikipedia.org/wiki/Protein-sparing_modified_fast, with most of my protein coming from high quality animal sources the most effective thing I've tried for improving body composition and function and raising GH/IGF1 to slightly above average while keeping blood sugar and triglycerides low and improving everything else associated with metabolic syndrome.  Having to make critical decisions in the absence of information specific to me regarding long term outcome, I'm going with what my eyes tell me is working best here and now.

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I brought up my individual case just to suggest the difficulty of applying general rules applicable to everyone.  I suppose I agree with the suggestions to avoid excess animal protein and excess carbs but what is excess can vary wildly person to person.  Some do very well with very high levels of carbohydrate intake while diabetics and those headed in that direction with significant indications of metabolic syndrome/insulin resistance tend to do better at much lower levels.  I basically agree with Tom's take on the paper regarding "risk alleles".  However, my expectation is that it will be a very long time before we have a complete enough understanding of them to suggest an optimum diet for someone based on genetic testing.  In the meantime I think it would be more prudent to focus on patterns of biomarkers and see how they respond to guided dietary experimentation.  Here's an example of this approach I think is fairly good given our current state of knowledge.



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This is a book I read recently, its authors (segal et Elinav) have been cited 2-3 times in this forum:


The Personalized Diet: The Pioneering Program to Lose Weight and Prevent Disease

Hardcover – December 26, 2017 by Eran Segal  (Author), Eran Elinav (Author), Eve Adamson (Contributor)


the only issue I have with this book that it goes into the practical scheme at 60% of the content.


In a few words: the authors led controlled trials to monitor individual glycaemic response to various foods. The result was puzzling, in that the individual variability in response tended to be pretty huge.

Their scheme is pretty simple, they suggest to measure blodd sugar at determined intervals after meals troughout the day and observe the results. I believe that lots of people in this forum are already doing this, but they systemize the procedure, as it were, giving benchmark values and giving importance especially to the peaks, or the delta glucose from baseline.


Their contention is that the published glicaemic indexes are average values and that usually inter individual variability is large, especially so in some kind of foods.


I've been monitoring myself a little and my thoughts that I am pretty glucose-tolerant might be confirmed, or maybe the foods I eat, although containing significant simple sugars, do not cause large spikes in my blood sugar. I'll have of course to go on especially after the seasonal change in dietary regime.



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