Venki Ramakrishnan shared the 2009 Nobel Prize in Chemistry for working out the structure of the ribosome, and is the author of the blockbuster bestseller, “Why we Die: The New Science of Ageing and the Quest for Immortality”. This long piece from him in the Scientific American comes at a time when immortality is turning into a business plan. “A growing number of tech billionaires are funding efforts not merely to slow aging but to defeat it altogether. Their goal is radical life extension and, ultimately, something approaching immortality.” His question is whether they can succeed. “Is there a biological reason that humans must die? And if not, could we one day live forever?”
Ramakrishnan starts by pointing out that aging is not fixed. Built from the same chemical parts, species live for very different lengths of time. “Mayflies may live only days, mice about two years, and bowhead whales and Greenland sharks for centuries.”His example for the extremes is hard to beat. “Galapagos tortoises live so long that one of them hobbling around today could have encountered Charles Darwin in 1835.” Nor is any of this random. “Lifespan is closely related to metabolism. Smaller animals generally have higher metabolic rates and shorter lives; larger animals tend to metabolize energy more slowly and live longer.”
However, evolution does not prefer longevity for its own sake. “Natural selection doesn’t care how long an organism lives. It favors traits that increase reproductive success.” Every species, he writes, “makes trade-offs in how it allocates resources among growth, reproduction and maintenance.” A mouse likely to be eaten gains nothing from investing in maintenance; a whale, slow to mature and hard to prey on, does. The same logic explains why “birds and bats often live much longer than similarly sized terrestrial mammals because flight reduces the risk of predation.”
But there is a catch, that biologists call ‘antagonistic pleiotropy’. Evolution “can also reward genes that are beneficial early in life even when they become harmful later,” so that “the same genes that promote rapid growth or prevent cancer during youth can contribute to aging later on.” Aging, in this view, “is not an adaptation in itself but an unintended consequence of evolutionary compromises,” and the upside is that every species has a ceiling, including humans. “Human life expectancy has roughly doubled over the past 150 years because of improvements in public health, nutrition and medicine,” he writes, but maximum lifespan has barely moved. “The longest documented human life is that of Jeanne Calment, who died at 122 in 1997. No one since then has lived past 120.” Getting much beyond that “would require altering the biology of aging itself.”
At the cellular level, the old picture of simple wear and tear is wrong. “Cells possess sophisticated systems for repairing damage, maintaining our repertoire of proteins, recycling components and regulating metabolism. Aging occurs not merely because damage accumulates but because these protective systems themselves become less effective over time.” Its hallmarks show up across the body, from “damage or changes to our DNA” to “dysfunction of mitochondria” and “reductions in stem cells,” all of them linked, so that “a disturbance in one often affects many others.” The encouraging part is that “there is no physical or chemical law preventing us from modifying these processes. The challenge is that aging is extraordinarily complex.”
The most effective approach is ‘caloric restriction’. “Animals given just enough calories to maintain adequate nutrition often remain healthier and live significantly longer,”appearing “biologically younger than their age,” because the deprivation “reduces protein synthesis and stimulates autophagy, the cellular recycling process that removes damaged molecules and organelles.” The catch is that few of us would want to. “Constant hunger, sensitivity to cold, impaired wound healing and reduced libido make strict caloric restriction difficult to sustain.” Hence the hunt for drugs that copy the effect without the misery – rapamycin, found in soil from Easter Island, which extends life in mice but is also “an immunosuppressant, raising concerns about infection and long-term safety”; metformin, whose benefits in healthy people are “mixed”; and the newer GLP-1 drugs, which help several organs but cost muscle.
A second front targets cellular senescence. “Cells experiencing damage or stress sometimes enter a senescent state in which they stop dividing and begin secreting inflammatory molecules,” and “early in life this response is beneficial, aiding development, wound healing and cancer prevention. With age, however, senescent cells accumulate faster than the body can remove them.” Clearing them out improves aging in mice, but he flags the risk, since “senescent cells serve a biological purpose, and eliminating them indiscriminately could lead to new problems.” He also describes a “somewhat bizarre” experiment in which old and young rats were surgically joined to share a blood supply, after which the old ones lived longer, a finding that spawned businesses selling young-donor plasma. His verdict is that “There is no convincing evidence that such procedures slow aging in humans.”
Slowing decline is one thing but reversing it is the real prize. Here the story runs through the embryo. “A major breakthrough came in 2006, when Japanese biologist Shinya Yamanaka discovered that activating just four genes could convert adult cells into pluripotent stem cells,” a discovery that “raised the possibility that if we can reset cellular age, perhaps we can reverse aging itself.” Full reprogramming is dangerous, since the cells can form tumours, so researchers use partial reprogramming, and “results in mice have been striking,” including one case in which a damaged optic nerve was regenerated. For all the obstacles that remain, he rates this “the most compelling route yet toward genuine rejuvenation, rather than merely slowing decline.”
Dr Ramakrisnan then turns cautious. Antiaging medicine, he notes, faces “a higher bar than treatments for life-threatening diseases.” A cancer patient will accept risk; healthy people “are unlikely to tolerate serious side effects from drugs they may have to take for decades.” Even the popular hope of a long healthspan followed by a quick end has thin support. “In many countries, people are living longer, yet the fraction of life spent with multiple chronic illnesses has increased.” His conclusion cautions against any single fix. “There is no scientific law against the idea, but nor is there any reason interstellar travel must be impossible. It’s just that the practical complexities are immense… It is unlikely that a single intervention could simply switch aging off without affecting us in other ways.”
What, then, actually works? The answer is familiar. While we wait for the science, “the best-supported tools for healthy aging remain the trio of diet, exercise and sleep,” to which he adds that “avoiding social isolation and having a sense of purpose are associated with better health and longevity.” Dull fundamentals which our grandmothers told us about still beat cutting edge research and fancy technology!
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