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April 11, 2021



The Best Remedy for Our Diseases? Aging Less
Some animals hardly deteriorate as they get older. New therapies could help humans to achieve the same healthy longevity.

April 10, 2021

Every year that you’re alive, your risk of dying increases by 10%. This starts out innocuously enough: In your 30s, your odds of death in any given year are less than one in 1,000. But compounding 10% per annum starts to add up frighteningly quickly: By age 90, if you’re lucky enough to make it that far, your odds of not making your 91st birthday are roughly one in six.

We all know, of course, that we’re more likely to die as we get older and accept this as a fact of nature. Those of us who make it far enough expect to be confronted with frailty, disease and death caused by our bodies’ degeneration with time. If you cast the net a bit wider, however, this fact of nature appears less immutable. Some species of tortoises, for example, have a risk of death that doesn’t seem to change with age in adulthood. Though these wrinkly, lumbering beasts might not seem like ideal ambassadors for aging well, by the statistical definition of aging—how fast your risk of death increases with time—these tortoises hardly age at all.

This phenomenon is known as “negligible senescence.” Some kinds of salamanders and fish, tiny pond creatures called hydra, and burrow-dwelling rodents called naked mole-rats all have a risk of death unrelated to how long ago they were born. This often means that they live much longer than closely related species. Mice might live to 3 years old but naked mole-rats can survive into their 30s.

The Galapagos tortoise is one of the most long-lived species.
The Galapagos tortoise is one of the most long-lived species.

A secret of the tortoises’ longevity is that their cells can divide more than twice as many times as human cells before becoming aged or “senescent.” Naked mole-rats are more enigmatic, aging in similar ways to us at the microscopic level; other biological mechanisms appear to keep them healthy regardless. The crucial result is that these animals don’t just live a long time, but they do so in good health. You would be hard-pressed to tell which adult naked mole-rats are the oldies. They maintain everything from muscle mass to fertility until extreme old age, scurrying around fit and healthy and even reproducing.

So do we humans have to age the way we do? Rapid progress in the biology of aging is leading us to wonder whether humans could take our first tentative steps towards negligible senescence by treating the aging process itself. The aim of biogerontologists working in this fast-developing field is to maximize not lifespan but healthspan: the number of years we spend free from disease, disability and impairment. No one wants to live to 130 if it includes a 50-year stint in a nursing home at the end. Extended healthy life is less attention-getting than eternal life, but pursuing preventive treatments that target the underlying cause of most human suffering could lead there and to a profound revolution in medicine.

Naked mole-rats can live 10 times as long as mice; it’s difficult to tell older ones apart from younger ones. .

Already, therapies to combat cell senescence—senolytics—are undergoing human trials. Senescent cells build up in our bodies as we get older and seem to accelerate the aging process as they accumulate. Drugs and genetic modifications that periodically remove them have been shown to make mice biologically younger: They live longer and healthier than untreated mice, with stronger muscles and hearts; delayed cancer, cataracts and cognitive decline; and even plumper skin and thicker, glossier fur.

There are currently at least 20 startups trying to transfer senolytics from the lab to the clinic. These efforts target specific diseases in which senescent cells are known to be key villains. A company called Unity Biotechnology is targeting these cells to combat age-related sight loss, while a team including scientists at the Mayo Clinic who first demonstrated senolytics in mice is working to use the same drug cocktail to treat age-related lung fibrosis.

The average 80-year-old is suffering from five different diagnoses and taking a similar number of medications to treat them.
Senolytics are the vanguard but close behind are dozens of different ways to slow or reverse aging in the lab, ranging from drugs and diets to gene and stem cell therapies. These treatments intervene in the molecular, cellular and biological underpinnings of the aging process, from the smallest scale in our biology (damage to DNA and protein molecules) to the largest (dysfunction across the immune system). They are aimed at slowing down multiple aspects of the process and at wide-ranging rejuvenation.

There have been some high-profile failures in the field. One was resveratrol, found in grapes and other sources. A company working on resveratrol, Sirtris, was acquired by drug giant GSK for $720 million in 2008 but closed down five years later. The path from lab bench to pill is filled with obstacles, and we can expect further setbacks, but with so many different therapies and a deeper understanding of the biology of aging, at least some of the new ideas are likely to succeed.

Our current approach to health in later life relies on treating individual diseases. If you find an unusual lump, you might go to your primary care doctor and be referred to oncologists who would attack a cancerous tumor with chemotherapy and surgery. But most cancers occur in older people, meaning that patients are often struggling with heart problems, diabetes or cognitive decline at the same time. The average 80-year-old is suffering from five different diagnoses and taking a similar number of medications to treat them. Surviving cancer just tees you up for the next age-related disease on the list.

In terms of lifespan, this per-disease approach has clear limits. It is calculated that even a complete cure for cancer would add less than three years to life expectancy, because so many other killers are waiting in the wings for older patients. In terms of healthspan, cancer treatment often leaves patients more frail than when they started.

The dream of biogerontology is to create medicines that will slow the aging process writ large in all of us. Cancers and heart disease, dementia, hearing and sight loss, and even wrinkles and gray hair are all caused by the same basic biological processes. Treating those processes before we get ill would allow us, like tortoises, to live in better health regardless of how old we are.

The vastly higher toll of Covid-19 on our seniors has brought into sharp relief the cost of aging to our health. At the same time, the rapid marshaling of science to develop vaccines for a novel disease has demonstrated how human ingenuity can overcome enormous health challenges. Such support for biogerontology could bring even more remarkable results.

Aging causes 85% of deaths in the U.S. but receives just 6% of government health research funding—substantially less than research into diseases like cancer and Alzheimer’s that aging causes. The amount of funding for research into actually treating aging is even smaller, while treating the chronic diseases of aging is a huge component of health costs.

With more funding, new treatments for aging could arrive in time for most people alive today. We could see senolytic drugs or other therapies in use within a decade. This makes it even more urgent to heed standard health advice to exercise, eat better and wear sunscreen. The longer you live in good health, the greater are the odds you will be alive to benefit from the new treatments and to live longer and healthier still. Before too long, it might not just be mice enjoying thicker, glossier fur into old age.



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