Epistemic status / declaration of interest: this is a semi-serious review of a really good recent book on advances in bio-gerontology, a fast-moving technical field, about which I am also writing a book. Please feel free to correct my sloppy solecisms and find my attempts at humour unfunny! Apologies to US readers for using the English spelling of ageing with an ‘e’.
So there’s this tortoise, a rocket strapped not very securely on its shell, with its fuse alight, while the hare looks sagely out as if to say ‘I told him it wouldn’t work’.
Is this a metaphor for healthy ageing, or a midlife crisis? Perhaps our reptilian hero, who appears to be grinning nervously, is about to live fast and die young; or is the firework a clue to the pyrotechnics within, as promised by the editorial blurbs?
We may never know what the Bloomsbury publishing marketing gurus had in mind. There is a hint on the cover of the hardback edition, that depicts a different much larger, wiser-looking tortoise sans explosives, so they might just have felt the urge to pep it up a bit for the paperback.
The back cover credits David Mann with the design and Getty Images with the picture. It also features an enigmatic quote, which is displayed even more prominently on the book’s sales page on the website of a famous tax-dodging tech giant named after a former rainforest (other good and bad bookshops are available).
'A stunner... If you haven't got this book in your house, I don't know why' Chris Evans.
This claim suggests an extraordinary lack of imagination, or perhaps concussion. I mean, I can think of lots of reasons you might not have it in your house or elsewhere. And who is this Chris Evans? The hunky star of Marvel’s Captain America? The loud-mouthed former breakfast DJ and TV presenter? The pioneering paediatric anaesthesist from UCL, who works just around the corner from Bloomsbury’s Bedford Square offices, or perhaps the mild-mannered tortoise?
Again, we may never know and of course none of this is Andrew Steele’s fault. After all he is only the author, so let’s cut him some slack, open the book and dive in.
The introduction opens in the Galápagos among those very giant tortoises, who it turns out enjoy negligible senescence. One female collected by Charles Darwin in 1930, transported to Australia and later named Harriet (when it was finally realised he was a she in 1960) lived healthily and apparently happily to the age of 175 before succumbing to sudden cardiac arrest in 2006.
Most other animals, including humans, do experience ageing, which Steele, a computational biologist, defines in actuarial terms as the increased risk of death as we grow older. Biologically, it is a progressive loss of homeostasis, the degradation of our organs due to accumulation of mutations, senescent and dysfunctional cells, compromised immune systems, inflamed tissues and general bodily wear and tear, which eventually combine to kill us. After the first few paragraphs, the gunpowder ignites, and for the next 300 pages, Steele’s narrative leaps and bounds along, more akin to a March hare than old Harriet.
Zig-zagging across the fields of demography, evolutionary biology, genomics, immunology and nutrition, it barely pauses for breath between the tangled bank of natural selection and the ethical thickets of experimental medicine. I really enjoy this racy style, but even with a degree in biosciences and over a decade working in health research communications, I confess I struggled to keep up at times. The challenge of writing about science for a lay readership is exacerbated when the subject is highly technical. Here’s a paragraph I’ve just found by opening the book more or less at random, on page 164:
“Though AMD and Parkinson’s treatments are leading the pack, there are plenty of other stem cell therapies close behind them. Diabetes might be next: we can make beta cells – the insulin-producing cells found in the pancreas that keep blood sugar under control – from iPSCs in the lab, and they can cure mice with diabetes. Human iPSCs have also been used to make ‘chondrocytes’ which make and repair the cartilage found in joints and they have been successfully used to regenerate the knees of rats with osteoarthritis. Earlier stage research in mice has shown that placing tiny droplets containing the precursors of smell-sensing neurons can restore sense of smell in mice whose own olfactory neurons have been damaged. Another study took cells purified from human urine (!), turned them into iPSCs, and used them to make dental precursor cells which grew into ‘tooth-like structures’ in mice.”
It helps to know that iPSCs are induced pluripotent stem cells, the development of which won Shinya Yamanaka and John Gurdon the 2012 Nobel Prize for Medicine, and that AMD is age-related macular degeneration, a common eye condition that affects many older people. Trying to digest so much data from diverse research projects in a few short sentences, I was left with a gnawing feeling of having bitten off more than I can chew with my puny tooth-like intellectual structures. Such a feast of information might be even more indigestible to readers new to the science.
It is also garnished liberally with cultural delicacies. Steele crams the history of stem cell research into a few pages, and then on page 166, we are into a fascinating discussion of how the involution of the thymus glands stimulates ageing, and how that can be arrested in male rodents and humans by castration. On that page alone we read about operatic castrati, mental institution inmates in Kansas and the cadre of naesi eunuchs who ran the Korean court for centuries and consistently outlived their testicled palace-mates. This is not an easy trial to replicate, for reasons that shouldn’t require explanation.
Ageless was published in 2020, so is reasonably up to date, even more so than Lifespan, the popular 2019 book by David Sinclair which Scott reviewed on ACX in December. It is also far more balanced and disinterested. Sinclair, who runs a big research centre at Harvard Medical School, needs to raise funds to support his team as well as various commercial interests. In contrast, Steele is a science writer formerly employed by the Francis Crick Institute, and is not directly working in bio-gerontology. He therefore doesn’t need to shill for sirtuins, resveratrol, big mitochondria or any of the other putative ‘cures’ for ageing on the market.
Steele also writes well on the practical and ethical dimensions of ageing research, and the challenges of translating basic science, often conducted in model organisms like nematodes or mice, into safe and effective treatments for humans. Here’s an excerpt from p201-2 of a longer section on efforts to exploit ‘heterochronic parabiosis’, the phenomenon by which old mice can be rejuvenated by transfusions of blood from younger mice:
“Others tried injecting youthful plasma into old mice and humans. There is some scientific rationale to trying this out just to see what happens: plasma transfusions are a relatively safe procedure, and positive result would provide proof of principle which could then be built upon, rather like the original parabiosis experiments. However human trials don’t appear to have been a resounding success – one in South Korea hoping to use young plasma to alleviate frailty began in 2015 and has yet to report any results, and a US trial gave infusions of young plasma to Alzheimer’s patients but didn’t succeed in turning back the disease.
The field has also got something of a bad name thanks to private companies trying to cash in on the euphoria around young blood. One colourful outfit called Ambrosia offers anyone over 25 the opportunity to receive a litre of youthful plasma for $8,000 (at the time of writing, a promotional offer also allows you to get two for $12,000 – buy one, get one half-price). In spite of reputed popularity among Bay Area tech execs and venture capitalists hoping to extend their time on Earth, the company temporarily ceased treatments after the FDA issued a statement warning that transfusions of young blood were risky and unproven. After spending nearly a year reassessing the rules, Ambrosia decided that their service is technically legal and resumed operations. The company also bills its treatments as a pay-to-participate trial, but there is (sic) no sign of any results at the time of writing. Worse, there isn’t a control group against which to compare transfusion recipients, making it very difficult to discern any effects the treatment may have – you can’t exactly give half your patients an infusion of saline solution if they’ve paid $6,000 for it, even if it would make for a fair test.”
The nexus of blood and cash obviously makes great stories, but it’s a genuinely interesting and developing sub-field of research and innovation. In March 2022, New Scientist reported the findings of Consuelo Borrás and her team at the University of Valencia in Spain, on the role of extracellular vesicles containing RNA and proteins transported in the blood. When researchers injected these into old mice, it reversed several signs of ageing, including boosting muscle strength and hair growth and improving coordination and endurance. Two control groups of mice given only saline injections, and those injected with extracellular vesicles from old mice, showed no such improvement.
However, two months after the injections, the effects had faded. The team is now giving mice monthly injections of vesicles to see if this extends lifespan, as well as trying to identify the specific components responsible for these effects. They are also planning a rather different human trial, to apply vesicles to pressure sores in elderly people via the skin, to see if they can help healing.
To declare a personal interest, Dr Borrás is one of several researchers who have very kindly agreed to interviews as contributions to my own forthcoming book on advances in bio-gerontology and the future of humanity. With their permission, I hope to keep the ACX community updated with material for discussion in advance of publication next year.
I hope by now you have a good flavour of the book, and even feel encouraged to read it. It does cover a lot of ground, and partly as a reminder to myself, I’ll devote the final part of this review to an orderly scamper through the main contents, with minimal commentary.
Part 1 chapter 1 deals with demography and death. The good news is that average life expectancy has soared in recent decades, especially in poorer countries, thanks to improved public health and lower child mortality. The bad news is that although we are mostly living longer and healthier lives, our last decades are blighted by cancers, heart disease, hypertension and other chronic diseases, causing pain, suffering and oh yes, still death. Steele, like other advocates, highlights that these may well be preventable.
Chapter 2 explores the origin of ageing as a by-product of natural selection. The more chance an organism has of being eaten by predators, the more evolution favours adaptations to breed early and fast. This is why rodents age and die much faster than birds of similar size, and perhaps why giant tortoises and Greenland sharks live so long. Save for a few lucky centenarians, even the healthiest humans tend to start falling apart at 70-80.
Chapter 3 looks at the birth of bio-gerontology, and early experiments in the genetics of nematode worms. Chapter 4 is about why we age, looking at molecular and cellular mechanisms of ageing. It posits nine kinds of mechanism, from DNA damage through telomere shortening, protein problems such as amyloids, signalling failures to cellular exhaustion.
Part 2 focuses on treating ageing, with four long chapters looking at in turn: potential treatments that get rid of old damaged cells and molecules that can cause problems; introducing new factors like stem cell therapy and gut microbiome; ‘running repairs’ such as parabiosis and telomere extensions; and finally ‘reprogramming’ ageing through genetic and epigenetic engineering.
Part 3 looks ahead to the next steps in the quest to overcome ageing and extend life. Here, Steele balances his passion for the literally life-saving potential of bio-gerontology with the practical, political, governance and funding problems. He also looks at some current exciting trials and some simple things most of us can do to improve our chances of living longer. These are unsurprising: good diet, eating well and not too much, physical activity, good sleep, gut health, oral hygiene and low blood pressure. He also recommends being a woman, and having very long-lived relatives.
We know that we are all doomed, but we do not yet know what the biological limits to ageing might be. Some organisms, such as the immortal jellyfish seem to be able to reverse ageing and reset their genomic clocks. Like Tolkein’s elves, although they may die, they do not grow old. Sinclair and others have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle and other tissues in cultured mammalian cells and rodent models.
Many advocates of anti-ageing science believe that human have the potential for far longer lifespans. Aubrey de Grey, the controversial founder of the SENS institute, famously claimed that the first human to live 1,000 years is probably already alive. It seems a bit of a leap, but if immortality is biologically possible, it is a realistic prospect, given time and technology.
With billionaire backing, advances in genomics and the vast computing power now available, we can expect the pace of discovery to accelerate. And as the more promising drugs and gene treatments currently in development are introduced over the next few decades, they may extend our lives, or those of our children, long enough for more radical transformation. Of course, many rationalist thinkers predict that sometime this century, humans may develop AGI that will be able to discover and deploy the technological resources to cure all human diseases, including ageing. That is as long as the AI doesn’t decide we are the problem and cures all human life first!
But even if radical life extension (or extinction) is not on the immediate horizon, there are tremendous gains to be made in healthy lifespan. If most of us can manage to live to 100 without undue pain, suffering and medical bills, it will be a huge achievement for science and humanity. While there are no drugs or supplements yet demonstrated to extend lifespan, there are promising developments in drugs that can simulate the effects of dietary restriction, and natural compounds that can stimulate protective cellular processes.
The oldest person alive at time of writing is Kane Tanaka, who celebrated her 119th birthday on 2 January 2022. Despite recurring bowel cancer, and a reported fondness for cola and chocolate, she has enjoyed generally good health, which she attributes to her Christian faith, family, sleep, good food and maths puzzles. Mrs Tanaka is a statistical outlier, but by no means unique; there are now an estimated 500 ‘supercentenarians’ over 110 in the world. Most of these are women, and many are Japanese.
The United Nations estimates the number of centenarians – people over 100 years old - in the world has quadrupled from around 150,000 in the year 2000 to 575,000 in 2020. For those who worry that longer life may merely mean more years of disease and disability, the evidence seems to point the other way. Centenarians tend to stay healthy well into their nineties, though this seems to be more luck than judgement.
The New England Centenarian Study, running since 1995 with a cohort of several hundred people over 100, has found that exceptional longevity runs strongly in families, and the degree of genetic influence upon survival increases in older ages. This probably involves many genetic variants with individually modest effects, that cumulatively slow ageing and decrease risk for ageing-related diseases such as heart disease, stroke, cancer, diabetes and Alzheimer’s.
However there are two genes that seem to be most strongly associated with longevity: APOE and FOXO3. APOE codes for a protein involved in cholesterol transport – the APOE2 variant appears to be protective against the diseases of ageing. FOXO3A, which occurs more frequently in centenarians, seems to simulate the beneficial effects of dietary restriction on cellular ageing. You can read a lot more about this in Ageless.
I am learning a lot from reading and reviewing books and articles like this, and although my own writing will inevitably be different in style, I hope to live up to Steele’s scrupulous regard for the evidence. This extends to the back of the book, which has 60 pages of detailed notes and references to research publication and studies. Many of these are ongoing, making it an invaluable source for further research, for which I am truly grateful.
Andrew Steele has written an exciting, optimistic, timely and valuable book that fully lives up to the hype on the cover, even if Chris Evans the tortoise is still looking at me in a funny way!
