Big Questions in Aging Research: What’s the Secret to Centenarians’ Longevity?

We know a lot about the basic mechanisms of human aging, but we don't know why some people live so long.

By Richard Faragher, Professor of Gerontology, University of Brighton, and Nir Barzilai, Professor of Medicine and Genetics, Albert Einstein College of Medicine

Translation | Xiaoye

If a man is 35 today, his chance of dying in the next decade is only 1.5%, but if he lives to be 75, his chance of dying before age 85 increases to 45% [1]. Clearly, aging is bad for your health. On the bright side, however, our understanding of the fundamental mechanisms that govern aging and the diseases of old age is advancing by leaps and bounds.

Some of the things that are closely related to life processes, such as stem cell supply and cell-to-cell communication, are sometimes called "markers of aging" [2]. They keep us healthy in the early years of life. But when these things start to fail, problems arise. Scientists are conducting clinical trials to determine whether targeting these markers can improve diabetic kidney disease [3], various aspects of immune function [4], and age-related lung scarring [5]. So far, progress is good.

Translator’s note: A review article published in Cell in 2013 [2] summarized nine major hallmarks of aging, including genomic instability, telomere attrition, epigenetic changes, loss of protein homeostasis, nutrient sensing dysfunction, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and changes in intercellular communication.

Unfortunately, there are still many big unanswered questions in the biology of aging. To assess the nature of these questions and how to address them, the American Association for Aging Research (AFAR) recently convened a series of meetings to bring together leading scientists and physicians. Experts agreed that understanding the unique biology of centenarians is a key challenge.

In the UK, these centenarians make up less than 0.02% of the population, yet they have already lived nearly 50 years longer than their peers, as the average life expectancy for people born in the 1920s was less than 55. How did they do it?

We know that centenarians live so long because they are exceptionally healthy. They stay healthy for about 30 years longer than most people, and when they get sick, it’s for only a short time. This “morbidity compression”[6] is obviously very beneficial to them, and to society as a whole. In the United States, the medical expenses of a centenarian in the last two years of his life are only one-third of those of a person who dies at age 70 (and most centenarians never even see a doctor).

The offspring of centenarians also tend to be much healthier than the population average, suggesting they have inherited some beneficial factors from their parents. But is this genetic or environmental?

Centenarians don't always live healthy lives

Are centenarians the epitome of healthy living? For the general public, watching your weight, not smoking, drinking moderately, and eating at least five portions of fruit and vegetables a day can help you live 14 years longer than someone who doesn’t pay any attention to health.[7] This difference is greater than the difference seen between the richest and poorest areas of the UK, so it makes sense that a good lifestyle would help people live past a century.

Surprisingly, this is not entirely true. One study[8] found that more than 60% of Ashkenazi Jewish centenarians have been heavy smokers for most of their lives, half of whom are also obese, less than half of whom exercise a little, and less than 3% of them are vegetarians. Moreover, the descendants of these centenarians are no more health-conscious than the average person.

Yet, these centenarians have only 50% of the risk of cardiovascular disease compared to their peers with similar food consumption, wealth, and weight [9]. In other words, these people are born with something different in their bodies.

A big secret

So is it possible that there are rare genetic factors? If so, there are two possible mechanisms. First, centenarians may carry unusual gene variants that extend lifespan; or, conversely, they may lack common gene variants that cause disease or injury in late life. Some studies, including our own [10], have shown that centenarians have as many bad gene variants as the average person.

Some people even carry two copies of a known Alzheimer’s risk gene (APOE4) and yet never develop the disease. So a reasonable hypothesis is that centenarians carry rare beneficial gene variants rather than lacking the disease-causing gene. The best available data are consistent with this conclusion.

More than 60% of centenarians have genetic changes that alter genes that regulate growth early in life. Centenarians are a unique example of a species that has been observed to live longer than other species. Most people know that small dogs live longer than large dogs[11], but few people realize that this is a common phenomenon in the animal kingdom. Dwarf ponies live longer than horses[12], and many laboratory mice with dwarfing mutations live longer than mice of normal size[13]. One potential explanation for this phenomenon is reduced levels of the growth hormone IGF-1, although centenarians are not necessarily shorter than other people[14].

Small dogs live longer than large dogs. Image credit: anetapics/Shutterstock

Clearly, growth hormone is essential early in life, but there is growing evidence that high levels of IGF-1 from middle to late life are associated with increased late-life disease[15]. The exact mechanism of action remains to be elucidated. However, among centenarians, women with the lowest growth hormone levels lived longer than those with the highest levels[16]. They also had better cognitive and muscle function.

That doesn't completely solve the problem, though. Centenarians are also unusual in other ways. For example, they tend to have good cholesterol levels, suggesting that longevity may have multiple causes.

In short, centenarians are the result of a "natural experiment." They show us that even if an individual is affected by risky genes or chooses to ignore health information, it is possible to live a healthier and longer life—as long as they have some rare mutations that are not yet understood.

Understanding exactly how these mechanisms work could help scientists develop new drugs or other interventions that target biological processes in key tissues at critical moments. If all this becomes possible, perhaps more of us will see the light of day in the next century. Until then, though, be cautious about following the life tips of centenarians.

References

[1] https://academic.oup.com/jnci/article/100/12/845/882914

[2]https://www.sciencedirect.com/science/article/pii/S0092867413006454#!

[3]https://www.sciencedirect.com/science/article/pii/S2352396419305912

[4] https://www.science.org/doi/10.1126/scitranslmed.aaq1564

[5]https://www.sciencedirect.com/science/article/pii/S2352396418306297

[6] https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.14222

[7]https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0630-6

[8] https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/j.1532-5415.2011.03498.x

[9] https://pubmed.ncbi.nlm.nih.gov/29050682/

[10] https://onlinelibrary.wiley.com/doi/10.1111/acel.13216

[11] https://onlinelibrary.wiley.com/doi/10.1111/acel.12737

[12] https://onlinelibrary.wiley.com/doi/10.1111/age.12416

[13] https://pubmed.ncbi.nlm.nih.gov/29653683/

[14] https://www.science.org/doi/10.1126/sciadv.1602025

[15] https://www.pnas.org/content/105/9/3438

[16] https://onlinelibrary.wiley.com/doi/10.1111/acel.12213

This article is translated from Why it's still a scientific mystery how some can live past 100 – and how to crack it

Original link: https://theconversation.com/why-its-still-a-scientific-mystery-how-some-can-live-past-100-and-how-to-crack-it-172020