Biological aging explains why life expectancy in Italy has doubled in just a century, rising from 40 to over 80 years. A century ago, families rarely lived long enough to see their grandchildren grow up, and adults barely past forty already looked elderly. Today the picture has changed: couples have few children, often only one. The classic demographic pyramid, wide at the base with children and narrow at the top with the elderly, has been reshaped. It now looks more like a vessel viewed bow-on: narrow at the base among the young, and widening through the middle toward the older age groups. Italy shares this demographic shift with Japan and most high-income countries. But why do we age, from a biological standpoint, and why doesn't living longer necessarily mean living better? Professor Simone Cenci, Associate Professor of Molecular Biology at UniSR, a geriatrician and group leader at IRCCS Ospedale San Raffaele, explains.
All living things age, though lifespan varies enormously across species: conifer forests that last thousands of years, bats that reach surprising longevity, insects that live only a few hours. Science defines biological aging as an intrinsic, progressive and cumulative process. It is intrinsic because it depends mainly on a biological clock built into the cells themselves. It is progressive and cumulative because it advances gradually, through an accumulation of cellular and bodily changes rather than sudden leaps.
Aging is inevitable. No lifestyle, however virtuous, can stop the process, though it can be slowed. Much of today's research in geroscience, the discipline dedicated to aging, focuses precisely on the possibility of changing its course.
The WHO reports a positive trend toward longer lives worldwide: global life expectancy keeps rising. Yet the increase in healthy life expectancy appears to owe more to a decline in mortality than to a rise in years lived without disability. In other words, we live longer because we die less, not because we live better. Much of this extra time is now threatened by chronic, inflammation-driven diseases, cardiovascular, metabolic and neurodegenerative conditions that often appear together.
Until recently, researchers assumed two distinct trajectories: “healthy” aging and “unhealthy” aging, each with its own mechanisms to study separately. We now know instead that biological aging itself, even without overt disease, is the main factor predisposing people to nearly all chronic conditions of old age, as shown by the work of Professor Luigi Ferrucci, scientific director of the US National Institute on Aging.
«Eighty years ago, a cancer diagnosis was a rare event. Today it affects roughly one man in two and one woman in three, because people now live long enough for DNA mutations to accumulate and translate into a higher cancer risk», Cenci explains. These shifts in the demographics of aging carry direct social and economic consequences: Italy has an estimated 7 to 8.5 million caregivers, professional carers and family members who informally look after an elderly relative, against roughly 170,000 practising doctors.
In this view, chronic diseases as different as osteoarthritis, osteoporosis, diabetes and dementia share the same underlying cellular mechanisms. «The disease simply speaks the different language of whichever organ stops working, but the mechanisms behind its onset are the same across organs. That could mean a therapy developed for one disease might also work for another», Cenci clarifies. This is the principle behind drug repurposing: redirecting medicines originally developed for one condition toward new therapeutic targets.
If aging is a universal phenomenon, it's worth asking what evolutionary purpose it serves, whether it helps preserve the species, for instance. The scientific evidence gathered so far doesn't support that idea. Picture an engineer designing a probe for a mission to Mars. To keep it working until the job is done, collecting data and transmitting it back to Earth, the engineer builds in self-repair systems. But once the mission ends, nobody bothers to plan the probe's destruction: maintenance simply stops, and the probe degrades on its own. «We are that probe in space», Cenci says, «and evolution has no reason to make us age, or not age. Yet over time, we lose our parts».
One of the theoretical pillars of geroscience is the disposable soma theory, formulated in 1977 by biologist Thomas Kirkwood. According to Kirkwood, organisms invest their available resources in staying healthy and fertile during the reproductive years. Once that phase ends, evolutionary pressure disappears entirely, neither favouring survival nor working against it. A complementary concept is antagonistic pleiotropy, in which the same biological mechanisms that protect us when young become harmful later in life. Inflammation is the clearest example: essential in early life for healing wounds and fighting off pathogens, the same process contributes, after age fifty, to many of the chronic diseases typical of aging.
The same holds for cellular senescence, the mechanism by which a cell stops proliferating to avoid turning cancerous. This too is a protective response, but the build-up of senescent cells in tissue over time creates a chronically inflamed environment that favours disease. «Because aging isn't a trait evolution preserved for some adaptive advantage, the good news is that, in principle, we can intervene to change it», Cenci notes.
Biological aging plays out differently in males and females. In nearly every human population, and in almost all wild mammals, females live longer on average than males. The gap is about four years and has held steady for decades, across very different cultures, ethnicities and lifestyles. «Women live longer because they age better, not because their behaviour is more virtuous», Cenci points out. The biological basis for this difference remains unclear, though some clues point to an evolutionary moment roughly half a billion years ago, when vertebrates developed three key features: a mineralised skeleton, an adaptive immune system based in the bone marrow, and the estrogen receptor, a protein that turned estrogen from a metabolic by-product into a true hormone.
Estrogen nourishes and supports the skeleton and the cells of the immune system, which explains why women experience a marked drop in bone density once ovarian function ends. Men also produce estrogen, converted from androgens, but in smaller amounts. That may help explain why male tissue ages earlier than female tissue, leading to very different clinical profiles between the sexes. Men more often develop early-onset cardiovascular and metabolic comorbidities, while women more frequently present with skeletal and joint diseases such as osteoporosis and osteoarthritis. Dementia, too, is more common among women, a reflection of their longer average lifespan rather than a biological difference in itself.
The gender gap is just as clear among centenarians: nine women for every man reaching at least a hundred, a ratio that climbs to nineteen to one among supercentenarians, people who have reached or passed 110 years of age. «When we stratify centenarians by health status, though, three distinct profiles emerge, in roughly equal proportions», Cenci observes. The first group, the escapers, develop almost no age-related disease at all, maintaining functional abilities comparable to people decades younger. The second, the delayers, develop the same diseases as the general population, but roughly twenty years later. The third group, the survivors, live with chronic conditions for up to thirty years without developing the organ complications one would expect. «That's a sign their tissues have adopted, over time, strategies that limit the damage», Cenci adds. «It's precisely in this last group that the female presence is even more pronounced».
A final line of research looks at longevity through a comparative lens across species. In mammals, lifespan correlates closely with body mass: a twenty-gram mouse lives about two years, a two-tonne whale about two hundred. Calculating a longevity quotient, correcting lifespan for expected body mass, brings almost every species into line around a constant value. «Humans, though, break sharply from that rule», Cenci remarks. «We live roughly three times longer than our body mass would predict».
Bats are even further off the scale, reaching a longevity quotient up to ten times the mammalian average for their size. They outlive even the naked mole rat, a burrowing rodent shielded from predation and widely studied for its unusual immune characteristics. Every night, bats endure a level of metabolic stress unmatched among mammals: during active flight, their heart rate can exceed 800 beats per minute, while body temperature climbs to 45–50°C. «Under those conditions, any other mammal would suffer cardiac arrest or, at the cellular level, protein denaturation, a lethal event for cells. Yet bats show no visible signs of aging, develop tumours at extremely low rates, and retain advanced cognitive abilities such as echolocation or complex social behaviour, until an age equivalent, in human terms, to several hundred years», Cenci recounts.
Professor Cenci's geroscience lab includes a group studying bats to understand which cellular mechanisms let them tolerate stress that would kill a human. The phenomenon is called hormesis: the capacity of a moderate, sub-lethal stress to trigger lasting protective cellular responses, the same logic behind regular physical exercise or vaccination. It may be no coincidence that the Chinese word for “bat”, bianfu, is a homophone of the word for “longevity”. Understanding how bats evolved such effective cellular resistance strategies is the goal of the international Bat1K project, which is sequencing the genome of every bat species to uncover the genetic basis of longevity. Its first phase, already complete, has produced over 100 reference genomes. «We're not so much after Harry Potter's elixir of life», Cenci concludes, «as the chance to add life to our years, as well as years to our life».
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