Forever young: what science can and can’t tell us about cheating ageing

Why We Die: The New Science of Ageing and the Quest for Immortality Venki Ramakrishnan Hodder (2024)
We are born; we grow up; we become an adult and perhaps reproduce. Then we might increasingly develop ailments or chronic diseases, before we decline and eventually — inevitably — die. These are the facts of life, at least hitherto, however much many of us might wish for them to be otherwise.
Perhaps things could be different. Progress in ageing research has opened up the prospect that ageing and death might be deferred, possibly even for hundreds of years, according to some people. Is that wishful thinking? The timely, illuminating book Why We Die by 2009 chemistry Nobel co-laureate Venki Ramakrishnan explains the science — and, importantly, separates fact from fiction.
Over the past century or so, better hygiene, improved living conditions and health-care innovations, such as antibiotics and vaccines, have seen human life expectancy more than double. But the maximal lifespan has hit a ceiling at about 120 years. And towards the end of their generally long lives, many people nowadays spend an extended period beset by the problems of ageing.
Halting ageing and death has been the subject of speculation, beliefs and myths for millennia. The great pyramids in ancient Egypt were built by people who thought the pharaohs would find new life; the quest for the ‘fountain of youth’ is a perennial feature of human storytelling. Modern science has revealed what that quest is up against. Ageing is what happens by default to organisms that have lived past the period of life during which they generally pass on their genes to the next generation. After that, no selective pressures stand in the way of processes of deterioration and decay.

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Research has identified many biological hallmarks of ageing: DNA accumulates damage; the ends of chromosomes get shorter; proteins clump together; organelles, including mitochondria, stop functioning properly; the number of stem cells falls; and organs become chronically inflamed. These issues mainly reflect increasing chemical damage to molecules that affect all cellular systems, including the maintenance, repair and renewal processes that would usually counteract such deterioration. This initiates a vicious cycle that eventually triggers cellular ageing, or senescence, and death, inescapably leading to an organism’s demise.
Ramakrishnan explains these fundamental processes of ageing in a laudably comprehensible, accessible manner (even if, for the completely unversed, some complex concepts do inevitably require some rereading). A basic question now for researchers is what the relationship is between everything that goes wrong. Is ageing caused by one or several factors, and which of those prevail? Although not all scientists agree, weighty evidence supports the idea that the ultimate cause is accumulating damage to DNA, through agents such as oxygen radicals, ultraviolet and X-ray radiation, cigarette smoke, chemotherapeutics, alcohol, many natural metabolites and even water. This insight is crucial for deriving reliable biological markers of ageing in tissues or blood. Such a feat has been accomplished through the ingenious identification of epigenetic clocks in our genome. But these insights are even more important for revealing targets that enable intervention in the ageing process.
Reports of advances in anti-ageing interventions, such as the discovery of ‘senolytics’ — compounds that eliminate senescent cells — have attracted wide public attention and considerable commercial interest. But even scientists cannot always discern whether a study’s findings are reliable or inaccurate, promising or only preliminary.
Despite not specializing in ageing research, Ramakrishnan provides many insights in Why We Die. He does this through extensive research: critically reading the literature, consulting with reliable specialists and, most importantly, using rational, independent thinking and common sense. His interviews with researchers in the field allow him to peek behind the curtains and obtain interesting information not found in textbooks or scientific journals. Why We Die is peppered with fascinating anecdotes, peculiar personalities and valuable historical perspectives, giving it an extra dimension beyond a summary of the state of the art.

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So what is truly hot and what is not? Dietary restriction has long been known to generally delay ageing and robustly extend lifespan, but it is not a popular practice, Ramakrishnan notes. He goes on to discuss the partially successful search for drugs that mimic its effects. Inhibition of a key metabolic enzyme, called mTOR, in many organisms moderately extends their lifespan, but in humans seems to have limited effect. Although not discussed by the author, GLP-1 receptor agonists, marketed for treating diabetes and obesity by lowering appetite and body weight, might provide a promising alternative.
The use of senolytics has raised people’s expectations, because they have a variety of benefits in mice. But cellular senescence takes many forms, and is also essential for development, the stress response and in the prevention of cancer, complicating application to humans. Such concerns also apply to the strategy of providing factors derived from the blood of young donors to old recipients, which research has shown to partly rejuvenate old mice. However, results are encouraging for studies on the reprogramming of adult mouse cells to stem-like cells by transiently expressing certain transcription factors that control sets of early developmental genes. Such techniques might be applied to humans in a distant future when safety issues are settled.
But rejuvenation strategies that replace cells will not be suitable for all tissue types. In particular, such methods would not work for the brain, because most neurons have to stay alive and functioning throughout our entire lifespan. This constitutes a major barrier, despite the development of cell-culture protocols for clusters of differentiated neurons known as minibrains. The name is overly optimistic, because these minibrains by no means encompass the enormous complexity of their real counterparts. Even more unlikely is the idea championed by some people that somebody’s brain or even whole body can be preserved by storing it in liquid nitrogen until technological advances can resurrect them. The degree of trust in such methods is perhaps similar to the Egyptians’ conviction that their pharaohs would be resurrected.
Why We Die is highly interesting for everyone, and certainly contains lessons for scientists, too. For instance, Ramakrishnan distinguishes DNA damage and DNA mutations. The processes that cause these changes are distinct and have different outcomes — ageing and cancer, respectively — and are still too often mixed up by specialists in ageing research. Another example is the focus in the field on changes that promote longevity. Investigations of animals with mutated genes that cause health problems prematurely or accelerate ageing might be equally, if not more, revealing.
This book could save a lot of money for investors in anti-ageing companies and for billionaires who, instead of wasting their capital on chasing non-existing elixirs of eternal life for personal benefit, could help humanity by supporting treatments that truly show promise. Further extending a healthy lifespan can come only from intervening in the basic mechanism of ageing, revealed by solid science.