Can a Reasonable Argument be Made for Variations in Human Longevity to be Significantly Driven by DNA Repair?

As I'm sure you are all aware, we humans do not exhibit a uniform pace of aging. Setting aside mortality caused by anything other than aging, the vast majority of recorded life spans at the present time fall within a range of three decades, 65-95. A comparatively tiny number of exceptional outliers age to death at younger or older ages. Some of this variation can be attributed to secondary aging, which is to say the way in which circumstances and lifestyle choices interact with the biology of aging. Visceral fat tissue and smoking cause greater chronic inflammation, accelerating all of the common age-related conditions, for example. On the other hand, calorie restriction modestly slows most aspects of aging. The rest is due to differences in primary aging, meaning intrinsic differences in genetics that lead to differences in the operation of cellular mechanisms that occur more independently of lifestyle and environment. Some human mutants have lower blood cholesterol, and thus slower onset of atherosclerosis, for example.

Most accelerated aging conditions take the form of a mutational malfunction in DNA repair - cells become damaged and dysfunctional much more rapidly than is the case in normal individuals. The present consensus, not unchallenged, is that stochastic mutation has a meaningful role in aging. This may be a matter of problematic acquired mutations in stem cells expanding widely throughout a tissue as a result of being inherited by daughter cells. If stochastic mutation is important in aging, then it may be reasonable to argue a role for variations in DNA repair mechanisms in the natural differences observed in human life span. Indeed, some past studies have done just that. It is very challenging to make a case for how large any given contribution to aging and longevity might be, however. Short of accurately and narrowly removing a specific contribution and watching to see what happens as a result, informed speculation is about the best that can be achieved.

Personally, I'm not convinced that there is all that much gold to be found in mining the causes of natural variation in human life span. Near all evidence to date (with one or two spectacular exceptions) suggests that individual genetic variations have at best modest effects, and more usually tiny and highly conditional effects. Variations correlated with longevity in one study usually don't appear in another, and "correlated" in this context might mean that it raises the odds of reaching the age of 100, while being so corroded by aging to a ghost of what you once were, to be 2% rather than 1%. This doesn't seem like a goal worth chasing when there are better options available. Instead of searching for ways to alter cellular metabolism in ways that would make more people live and age like today's centenarians, the research community should be finding ways to reverse the mechanisms of aging - to repair the damage, to restore the normal operation of youthful metabolism.

Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest-Old Population

Longevity is usually defined as living until life expectancy that is typically over 85 years old. Exceptional longevity such as centenarians is considered when one is more than 95 years old with a healthy life. Several researchers have emphasized the importance of in-depth studies on longevity to cope with an aging society because such studies could suggest various biomedical clues for living a long and healthy life. Oldest-old individuals, often centenarians, represent an adequate model to investigate the complex phenotype of healthy longevity. Among enormous population-based studies on centenarians, one major focus is on people with exceptionally long lives without functional impairment. Several landmark studies on healthy centenarians have found that the progression of major diseases such as cancer, cardiovascular disease, and stroke is delayed in the oldest group compared to that in the other younger or same-aged control groups, suggesting a substantial relationship between healthspan and longevity.

Although successful longevity traits are modulated by various factors, such as environmental, behavioral, and/or endogenous causes, genetic factor might be a major factor that contributes to healthy aging. Within the past few decades, many researchers have tried to identify longevity-associated genes using diverse species, ranging from less complex organisms to higher organisms. With development in genomic technology, genetic factors associated with longevity have been suggested in human population studies and human genome-wide association studies. It has been found that variants of APOE and FOXO3A are highly associated with longevity. This finding has been consistently replicated in many different population-based studies. Despite the complexity of healthy longevity in human due to various influences, genetic factors are thought to be exceedingly important to understand the genetic basis of longevity.

Accumulation of DNA damage is associated with functional decline in the aging process. Thus, maintenance of genomic integrity might be a crucial factor for healthy life and longevity. Genome instability generally increases with age. DNA repair machineries control genome stability. Previous studies on centenarians have shown that oldest-old population have enhanced DNA repair activity with significant lower frequency in genomic and cellular damage compared to their younger counterparts. Thus, DNA repair plays an important role in understanding exceptionally long-lived individuals.

In this review, we focus on major DNA repair machineries associated with longevity. We also explored longevity-associated population studies using genome-wide approaches. With brief introductions of genomic databases in aging and longevity field, ample genomic resources of normal long-lived human population were utilized for DNA repair-focused approach. Herein, we suggest a new aspect of longevity study to investigate the complex interplay between DNA repair and longevity by processing human genetic variations based on previous studies, providing a brief interpretation of their molecular networks.

Comments

DNA damage and our ability to make perfect copies is looking very likely to be a primary cause of aging and correlates directly with lifespan in multiple species. There is a reason it sits at the top of the Hallmarks of aging and I think the case for DNA damage has only gotten stronger in the past years.

Posted by: Steve Hill at June 6th, 2018 6:40 AM

@Steve Hill or @Reason
Are there any studies looking at up-regulation of DNA repair in iPSCs/PSCs and their effects?

Posted by: Chris at June 6th, 2018 9:14 AM

@Chris: None spring to mind. That doesn't mean they don't exist.

Posted by: Reason at June 6th, 2018 3:14 PM

This Kim article on DNA repair genes is similar to an article my Miook 2014, Genomic Maintenance and human longevity, in which they even cover a few of the same genes and SNP's. I checked my DNA results from 23andme and found that I have many of the good SNP alleles for DNA Repair in these two articles. To be sure, I have a few bad alleles as well, but the vast majority are good for longevity and lifespan purposes. I believe real longevity benefits can come from this line of research and scientific investigations. We are certainly living in a fantastic time in terms of life extension, I can hardly wait for the next advanced life extension therapies. Now I see some companies are selling stem cell pills, and claim great benefits, but I am cautious and do not plan to try them until there is good scientific evidence they are working.

Posted by: Biotechy Marcks at June 6th, 2018 6:55 PM

@Chris
Thanks for posting that interesting question; it prompted me to do a PubMed search and find my reading material for the day (in addition to the FA blog, of course):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332618/

Posted by: CD at June 7th, 2018 10:11 AM

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