Ageing – not cancer, not heart disease – is the world's leading cause of death and suffering. We accept as inevitable that as we get older our bodies and minds begin to deteriorate, and we are increasingly likely to be struck by dementia or disease. Ageing is so deeply ingrained in human experience that we never think to ask: is it necessary?

Biologists, on the other hand, have been investigating that question for years.

Ageless introduces us to the cutting-edge research that is paving the way for a revolution in medicine. It takes us inside the laboratories where scientists are studying every aspect of the body – DNA, mitochondria, stem cells, our immune systems, even longevity genes that have helped animals to a tenfold increase in lifespan – all in an effort to forestall or reverse our decline.

Computational biologist Andrew Steele explains what is happening as we age and practical ways we can help slow down the process. He reveals how understanding the scientific implications of ageing could lead to the greatest discovery in the history of medicine – one that has the potential to improve billions of lives, save trillions of dollars, and transform the human condition.

100 highlights from Ageless

• by 90, your odds of not making your 91st birthday are one in six
• ageing is the exponential increase in death and suffering with time
• being old is the single biggest risk factor for cancer, heart disease, stroke, and dementia
• half of people aged 65 have two or more long-term conditions
• creatures from all over the tree of life live longer and healthier if fed significantly less than normal
• the aim of anti-ageing medicine is to keep us fit and disease-free for longer
• a single letter of DNA can extend a worm’s lifespan tenfold
• a complete cure for cancer would add less than three years to life expectancy
• it’s quite likely that a few ancient humans did make it into their sixties or seventies
• maximum global life expectancy has increased by three months every year since 1840
• by 2050, over-65s will make up one in six of the global population
• typical rich countries like the UK and Germany spend roughly 10 per cent of GDP on healthcare
• the doubling of human life expectancy since the start of the 1800s has been achieved without any treatments for ageing
• evolution’s inability to keep old animals fit is because they are less likely to have children (because of extrinsic mortality)
• antagonistic pleiotropy is the idea that genes have multiple effects allowing them to conspire to aid reproduction in early life, but go on to cause problems as the animal gets older
• naked mole-rats are almost cancer-proof, in stark contrast to mice, and resistant to neurodegenerative disease
• negligible senescence doesn’t break the laws of physics nor any laws of biology
• dietary restriction did seem to increase healthspan in two rhesus macaques studies, but the effects on lifespan were more ambiguous
• [if it had a significant impact on humans] there would be some ascetic religious sect living twice as long as the rest of us
• evolution has selected for animals who allocate more resources to carefully maintaining their bodies when times are tight
• heartbeats per lifetime is remarkably constant, from rats and mice to elephants and whales - we each get about one billion beats
• ageing isn’t one single thing – but nor is it thousands
• every cell in your body suffers up to 100,000 assaults on its genetic code every day
• when telomeres become critically short, they send out alert signals which stop a cell from dividing
• an individual protein molecule, hard at work inside a cell, will typically last a few days
• age-related diseases can be triggered by problems with autophagy (a way that cells get rid of rubbish)
• sugars are very keen to glue themselves to proteins in a process called glycation
• not only are there hundreds of different types of cells, but those cells need to do different things at different times
• multiple studies have now shown that epigenetic age acceleration is bad news
• cellular senescence exists as an anti-cancer mechanism
• only a few per cent of cells turn senescent, even in very old animals or people
• mitochondria frequently undergo ‘fusion’ and ‘fission’ events
• there tend to be fewer of them in older animals’ cells, and those mitochondria produce less energy
• dysfunctional mitochondria show up in diseases like Parkinson’s and Alzheimer’s
• mice genetically engineered to have extra copies of anti-free-radical genes live no longer than normal mice
• increasing dysfunction in signalling is part of the reason why ageing all seems to happen at once
• a rich, varied population of gut flora is good news
• as we age, HSCs become less effective at replenishing our blood cells
• olfactory receptor neurons die relatively frequently and rely on stem cells to replace them
• barely any of the thymus remains after the age of 60
• a handful of memory T-cells can expand to form a clone army of millions
• heart attacks and strokes caused by atherosclerotic plaques are behind something like one in five deaths
• giving old mice Dasatinib plus Quercetin basically makes them biologically younger
• more than twenty companies are working to move the killing of senescent cells
• a risk that removing senescent cells in some tissues could have unintended side effects
• Rapamycin slows cell death and improves cognitive performance in the brains of mouse models
• resTORbio is trialling rapalogue called everolimus and a new mTOR inhibitor called RTB101
• autophagy takes place in compartments in the cell called lysosomes
• we need to provide new enzymes which can help lysosomes deal with garbage they can’t currently tackle
• Ichor Therapeutics got as far as injecting a modified version of it into the eyes of mice and demonstrated that it rapidly cleared out both A2E
• occurrence of Alzheimer’s disease rises even faster than risk of death after 60
• there have now been well over one million HSC (aka bone marrow) transplants globally
• two trials in 2018 used stem cells to make RPE cells and implant them into patients’ eyes
• Intervene Immune used a combination of human growth hormone (HGH) with DHEA and metformin - thymuses look less fatty and have more T-cells
• using a gene called FOXN1 is a more direct way to induce thymic rejuvenation
• a revitalised thymus might not be enough to mount a strong immune response if the lymph nodes aren’t in good shape
• we might all be periodically popping tablets of freeze-dried faecal matter to keep our guts in top condition
• collagen is our most abundant protein, contributing two or three kilos to the average adult’s bodyweight
• modifications which mostly don’t crosslink the collagen might be more important than AGEs
• telomeres seem to be a key component of our cellular anti-cancer mechanisms
• old cells aren’t irreversibly decrepit
• human trials of injecting youthful plasma don’t appear to have been a resounding success
• Conboys tried dialling down the activity of TGF- beta
• urolithin A seen to improve mitochondrial function in people over 60
• adding an extra copy of p53 causes symptoms of accelerated ageing and reduces lifespan in mice
• most cells in your body acquire around ten to fifty DNA mutations every year you’re alive.
• skin of four people over the age of 50, which found that 20–30 per cent of cells contained a driver mutation
• what’s good for the survival of an individual cell isn’t necessarily good for the organism as a whole
• the degree of ‘heritability’ of longevity could be overestimated as people don’t usually pick their partner entirely at random
• married couples’ lifespans were more closely correlated than the lifespans of opposite-gendered children
• female centenarians outnumber males by over five to one
• which version you have of APOE gene has a huge effect on your odds of both cardiovascular problems and dementia
• variants of FOXO3 gene associated with extreme longevity in human centenarians
• PCSK9 mutation results in a staggering 88 per cent reduction in the risk of heart disease
• Klotho and FGF21 don’t play nicely together
• iPSCs are epigenetically zero years old
• modified versions of CRISPR that can alter epigenetic marks at multiple locations in our DNA simultaneously
• to truly cure ageing, we need to take a more holistic, ‘systems biology’ approach
• in silico biomedicine will eventually allow us to test all kinds of theories far more quickly and reproducibly than a messy lab
• our ability to collect the kinds of data we need is growing incredibly quickly
• curing ageing is a hugely important humanitarian goal
• a treatment for ageing could delay all cancers, as well as heart disease, stroke and dementia
• exercising improves health even in 80-somethings
• stopping smoking at 60 will increase your life expectancy by about three years
• ‘beer belly’ look results from fat in our abdomen between our organs, i.e. inflammatory visceral fat
• Okinawans only live about a year longer than people in the rest of Japan
• if you were thinking of trying DR or any of its variants, you’d be well advised to talk to your doctor first
• sarcopenia can be substantially reversed by resistance training
• getting more than eight hours of sleep is associated with a larger increased risk of death than getting too little
• the reduced burden of infection reduces the cumulative burden of inflammation
• getting sunburn just once every two years is associated with increased cancer risk
• a resting heart rate of 100 bpm instead of 60 approximately doubles your risk of death
• you have to be at increased risk of heart attack before daily aspirin is worth taking
• though women live longer, they tend to do so with worse health on average
• increasing our healthspan with treatments for ageing would be a vast net ethical positive
• a slowing of ageing resulting in a five-year increase in lifespan and healthspan would be worth $180 trillion, just considering the health benefits to the US population
• a trial of a meaningful anti-ageing treatment could theoretically be completed with just a few hundred patients, two years, and perhaps a few million dollars
• lots of drugs which work flawlessly in mouse models fail to translate to human success
• doing nothing can sometimes come with greater risks than doing something
• it’s time for a mission-driven medical moonshot – a massively funded, international programme of research to intervene in the ageing process

A world without ageing

There is also a FREE bonus chapter covering the ethics of curing ageing in a bit more detail - available here: https://andrewsteele.co.uk/ageless/ethics/a-world-without-ageing/

And here are a further 10 key points from that chapter:

• in the 19th century, would critics have argued that cholera and tuberculosis were ‘just a natural part of being alive’?
• if we lived in a society where there was no ageing, and one of these issues [raised against curing ageing], would you invent ageing to solve it?
• overpopulation suggests that our concern is too many people, when actually the issue is the amount of resources we use
• more people mean more potential for happiness and human flourishing
• inequality of access is true today of medicines from basic vaccines and antibiotics to cutting-edge cancer drugs
• therapies against ageing are also likely to be assisted by tremendous economies of scale, because the market is literally everyone
• one calculation suggested that completely curing ageing would only add 3.6 years to a dictator’s life expectancy
• influential jobs could come with a time-limited tenure
• if dying in a car crash at 30 would rob someone of 170 years of life, that would provide a strong incentive to improve vehicle safety
• death could be seen as an incentive to cash out, stop striving, and spend a few years enjoying what you’ve earned before mortality overtakes you