Why it’s still a scientific mystery how some can live past 100 — and how to crack it?

A 35-year-old man has only a 1.5% chance of dying in the next ten years. But the same 75-year-old man has a 45% chance of dying before he turns 85. It is clear that aging is bad for our health. On the bright side, we have made unprecedented progress in understanding the fundamental mechanisms that control aging and disease in later life.

A pair of closely linked biological processes, known as the “markers of aging,” including our stock of stem cells and communication between cells, keep us healthy early in life — with problems that arise as they begin to deteriorate. to fail. Clinical trials are underway to see if targeting some of these features can improve diabetic kidney disease, aspects of immune function, and age-related scarring of the lungs. So far, so good.

Unfortunately, there remain big, unanswered questions in the biology of aging. To evaluate what these are and how they can be addressed, the American Federation For Aging Research, a charity, recently organized a series of meetings for leading scientists and physicians. The experts agreed that understanding what is so special about the biology of humans surviving more than a century is now a major challenge.

These centenarians make up less than 0.02% of the UK population, but have exceeded the life expectancy of their peers by nearly 50 years (babies born in the 1920s typically had a life expectancy of less than 55 years). How are they doing?

We know centenarians live so long because they are exceptionally healthy. They stay in good health for about 30 years longer than most normal people and when they do eventually get sick, they are only sick for a very short time. This “compression of morbidity” is obviously good for them, but it also benefits society as a whole. In the US, the cost of medical care for a centenarian in the last two years of life is about one-third that of someone who dies in their 70s (a time when most centenarians don’t even need to see a doctor).

The children of centenarians are also much healthier than average, indicating that they inherit something useful from their parents. But is this genetic or ecological?

Centenarians aren’t always health conscious

Are centenarians the poster child for a healthy lifestyle? For the general population, watching your weight, not smoking, drinking moderately, and eating at least five servings of fruits and vegetables a day can extend life expectancy by up to 14 years compared to someone who does none of these things. This difference is greater than the difference between the least and most deprived areas in the UK, so it would intuitively be expected to play a role in survival over a century.

But amazingly, this doesn’t have to be the case. One study found that up to 60% of Ashkenazi Jewish centenarians have smoked heavily for most of their lives, half have been obese during the same period, less than half engage in even moderate exercise, and less than 3% are vegetarian . Nor do the children of centenarians seem more health-conscious than the general population.

However, compared to peers with the same food consumption, wealth and body weight, they have half the prevalence of cardiovascular disease. There is something naturally exceptional about these people.

The big secret

Could it have to do with rare genetics? If so, there are two ways this could work. Centenarians may carry unusual genetic variants that extend lifespan, or instead, they may lack common ones that cause disease and disability later in life. Several studies, including our own work, have shown that centenarians have as many bad genetic variants as the general population.

Some even carry two copies of the greatest known common risk gene for Alzheimer’s disease (APOE4), but still don’t get the disease. Thus, a plausible working hypothesis is that centenarians carry rare, beneficial genetic variations rather than a lack of adverse ones. And the best available data is in line with this.

More than 60% of centenarians have genetic changes that alter the genes that regulate growth in early life. This implies that these remarkable humans are human examples of a kind of life extension seen in other species. Most people know that small dogs tend to live longer than large ones, but fewer people are aware that this is a common phenomenon in the animal kingdom. Ponies can live longer than horses, and many species of lab mice with dwarf mutations live longer than their full-sized counterparts. One possible cause of this is decreased levels of the growth hormone IGF-1, although centenarians aren’t necessarily shorter than the rest of us.

Small dogs live longer than large ones.

It is clear that growth hormone is needed early in life, but there is mounting evidence that high levels of IGF-1 in mid to late life are associated with more disease later in life. The detailed mechanisms underlying this remain an open question, but even among centenarians, women with the lowest growth hormone levels live longer than women with the highest. They also have better cognitive and muscle function.

That doesn’t solve the problem, however. Centenarians differ from the rest of us in other ways too. For example, they usually have good cholesterol levels — suggesting that there could be several reasons for their longevity.

After all, centenarians are “natural experiments” that show us that it’s possible to live in excellent health even if you’ve been handed a risky genetic hand and chose not to pay attention to health messages — but only if you have rare, bad understood mutations.

Understanding exactly how these work would require scientists to develop new drugs or other interventions that target biological processes at the right time in the right tissues. If these become a reality, perhaps more of us than we think will enter the next century. Until then, don’t take healthy lifestyle tips from centenarians.

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