Summary: Ageless By Andrew Steele
Summary: Ageless By Andrew Steele

Summary: Ageless By Andrew Steele

Given that ageing is a multifaceted process, treating it is going to require a portfolio approach. We will look at how we could intervene in each aspect of the ageing process, with treatments that range from the currently hypothetical, to some nearly ready for deployment.


#1 Out with the old

The first is probably the most intuitive: the removal of bad stuff which accumulates with age. Some of the hallmarks of ageing are simply things which build up in our body as we get older and go on to cause the diseases and dysfunctions of old age. Thus, we need to devise ways to get rid of them.

There are three hallmarks which follow this pattern: aged, senescent cells, whose numbers slowly increase with age; defective proteins and other junk that hangs around inside cells and slowly causes them to work less effectively; and misfolded proteins called amyloids which accumulate both within and between cells and gradually cause problems from heart failure to dementia. The most obvious way to tackle these problems is to remove them at their source.

Killing senescent cells

senescent cells slowly accumulate in our tissues as we get older. Their name literally means aged cells, and senescence happens to cells whose telomeres are too short, that have suffered too much damage to their DNA, or are just generally under catastrophic levels of cellular stress. As a result, they slam on the brakes and stop dividing for safety reasons. It’s probably better than the alternative, which could be to turn cancerous, but the senescent state is far from benign: the cell pumps out molecules which fuel chronic inflammation around the body and can turn nearby cells senescent, too, or, ironically, cancerous. If not rapidly removed by the immune system, senescent cells fester, worsening both their local environment and the state of our bodies as a whole.

If we can get senolytics working in people, it will open up a cornucopia of new therapeutic options for diseases. It will also provide us with an irrefutable demonstration of the principle behind biogerontology: intervening in the ageing process can pay dividends for life and health. Perhaps, a senolytic could well be the first true anti-ageing potion to pass your lips.

Reinventing recycling: upgrading autophagy

a reduction in autophagy – the ‘self-eating’ process of cellular recycling which clears up broken proteins, damaged mitochondria and more – is likely to be central to the ageing process. Autophagy is our body’s own way of getting rid of junk, so could we take advantage of this natural system to keep our cells pristine?

Given that dietary restriction (DR) increases levels of autophagy, eating substantially less could be one approach to activating the process and slowing our own ageing. However, it would be even better if we could find some way to mimic the biological effects of restricting diet, but with less of the tedious abstinence. Enter ‘DR mimetics’: drugs which activate many of the same mechanisms as DR itself (including autophagy) without the need to eat less.


one nasty property of some proteins is that they aggregate into amyloids. These are proteins which, misfolded in particular unfortunate ways, gain the ability to stick together into clumps. Where the normal version of a protein will happily potter around doing its thing and minding its own business, an amyloid-prone misfolded version will seek out others like itself and latch on, in a kind of protein clone conga. Individual strings of amyloid are known as fibrils and they can aggregate into larger structures called plaques.

Plaques are most commonly associated with Alzheimer’s disease. Perhaps we could all get injections of anti-plaque drugs at regular intervals to prevent the build-up of toxic aggregates or, even better, be immunised against many different amyloids in childhood along with measles and diphtheria. Intervening before we’re old and diseases are too far advanced is exactly what the treatment of ageing should be about, and all of these therapies have the potential to be used preventatively.


#2 In with the new

There are some aspects of our ageing biology where getting rid of the bad actors won’t be a sufficient therapy unless we can replace them with something better. For example, though the aged immune system can be dysfunctional and put us at greater risk of infectious diseases and cancer, it’s better than the alternative: the only thing worse than having an ageing immune system is having no immune system at all.

Thus, we need to come up with ways to reinforce our ailing defences, and far more besides, providing our biology with a helping hand to reverse some of the decline of ageing.

Stem cell therapy

Stem cell therapy is one of the hottest areas in medicine, and harnessing stem cells for treatments is very likely to be a key weapon in our arsenal against ageing. Stem cells will help to replenish cells that are lost during the ageing process, playing a role in diseases from age-related blindness to diabetes and Parkinson’s.

However, given the hype which often surrounds it, stem cell therapy is frequently misunderstood. The term ‘stem cell’ is thrown around by charlatans who will take desperate patients to shiny, semi-regulated clinics and infuse them with mysterious solutions to ‘cure’ all kinds of different ailments. ‘Stem cells’ aren’t a single thing, nor are they some kind of elixir where a single treatment will fix many different diseases or undo the ravages of time systemically. In order to understand the huge, genuine potential of these therapies, we need to understand exactly what stem cells are, and therefore what we can expect them to do. Getting the right cells to the right place at the right time is key to using them for regenerative medicine.

Improving immunity

One place where stem cells and other rejuvenative therapies will be of use is the immune system. A good place to start is the thymus – the small organ just behind your breastbone where T cells are trained, and which undergoes a programmed decline starting in childhood. The process of useful thymic tissue turning to useless fat is known as ‘involution’ and it’s a surprisingly malleable process. Of the various ways to stop the thymus from involuting, or even reverse the process, probably the best-studied is sterilisation: both surgical removal of the testes or ovaries and drugs that stop the action of sex hormones increase the volume of the thymus in mice.

Though it might prove difficult to get volunteers for a clinical trial of sterilisation in humans, there are some fascinating studies that use historical evidence to try to work out its effects on longevity.

Modifying the microbiome

Given the synergistic relationship between our immune cells and gut flora, another thing an improved immune system might help with is our microbiome, maintaining its balance later into life and reducing chronic inflammation. However,

introducing the microbiome as the new kid among the hallmarks of ageing, we are only just beginning to understand the many factors that affect the health of our microbes, and how their health affects ours. There are probably situations where the quickest intervention is one which deals with the microbiome directly, allowing beneficial bacteria to help the rest of our body out.

There are various ways to try to restore balance to the microbiome. The simplest is probiotics, which you might be familiar with from the dairy aisle of your local supermarket. Probiotics seek to introduce live microorganisms into your guts when you simply eat or drink a product containing them.

Keeping protein pristine

Collagen is a structural protein whose name you may recognise from (often questionable) claims on the labels of skin and face creams. As with many not-quite-scientific claims, there is a grain of truth here: collagen is the most important protein in the structure of skin, and indeed many other tissues in the body, from blood vessels to bones. It’s our most abundant protein, contributing two or three kilos to the average adult’s bodyweight, and lasts for a surprisingly long time: current estimates suggest that it takes years for the collagen in your skin to be ‘turned over’ (the biological term for being broken down and replaced), and collagen in cartilage, which provides the smooth padding between bones at our joints, may last a lifetime.


#3 Running repairs

Sometimes the best approach to fixing a hallmark of ageing is neither removal nor replacement, but repair. Our DNA is a case in point: our cells wouldn’t last long without their molecular instructions, and replacing the two metres of the stuff in tens of trillions of cells would be somewhere between impractical and impossible. That means, from trimmed telomeres to mutations, we’re going to have to find ways to fix DNA while it’s still in our cells.

Telomere extensions

Every time a cell divides, its telomeres get shorter. Since many of our tissues rely on dividing cells to replenish them, their telomeres eventually become ‘critically short’, leading them to cell suicide or senescence. People with shorter telomeres tend to die sooner than those with longer ones. Is there a way to undo the erosion of our DNA’s protective end caps and, in doing so, extend our lives?

Experiments in mice present an increasingly watertight case that telomerase, wielded judiciously, need not be a double-edged sword, and there’s no obvious impediment to trying these therapies out in people. And, if they work, we can move from walking the telomerase tightrope with cancer on one side and degenerative diseases on the other, to dancing along it, protected from both.

Can young blood teach old cells new tricks?

One of the many vital functions of blood is to act as a telecommunications network for the body, ferrying dissolved chemicals which act as messengers that can affect how cells behave throughout the body. Watching what happens when a young mouse is confronted with old blood, or an old mouse is given a refreshing blast of the young stuff, has given us fresh insight into how the effect of systemic, internal factors can drive ageing. It also provides inspiration for new treatments – which thankfully won’t involve sewing old people to teenagers

Whether we will be visiting a plasmapheresis clinic every so often for a blood factor detox, taking drugs to rebalance our cellular signals, or being infused with exosomes is yet to be determined – but fixing faltering signals is likely to be an important part of our anti-ageing arsenal.

Powering up mitochondria

The decline of mitochondria, the herd of semi-autonomous energy generators which can be found inside our cells, is responsible for aspects of ageing around the body. There are fewer mitochondria in older cells, and those that remain are less effective at producing energy. The problems are especially acute in places where cells use a lot of energy like the brain, heart and muscles; mitochondria are almost certainly important in Parkinson’s disease, and there’s increasing evidence of their effects in other conditions too. Developing therapies to help out our mitochondria might thus alleviate many of the problems of old age.

we’ve got quite a few options when it comes to trying to slow or reverse the contribution of mitochondria to ageing, but we’re not entirely sure which will work best. This is partly because we still don’t have a complete picture of what happens to our mitochondria as we get older. In the short term, treatments might include mitochondrially targeted antioxidants to mop up the free radicals they produce, or supplements, like urolithin A, to ramp up our bodies’ own quality-control mechanisms. In the long run, it might be possible to re-engineer our biology to make sure that mitochondrial mutations no longer matter, eradicating their contribution to degenerative ageing – a goal well worth expending significant energy to achieve.

Repelling the attack of the clones

Damage to our DNA, and the mutations that result from it, could be some of the hardest age-related damage we need to fix in our bodies. The first approach we could take is probably the most obvious: repair. The second relies on understanding exactly how mutations cause problems in our ageing bodies, and learning how recent developments in DNA sequencing could overturn old ideas about why mutations matter

Thankfully, our understanding of the prevalence and type of mutations in ageing will increase dramatically in the near future. Genome sequencing is now cheaper than ever, and interest in accumulation of mutations is coming not only from the ageing research community, but the cancer research community, too. Those of us interested in curing ageing need to make sure that this work explores the contribution of mutations to degeneration as well as cancer, and ensure that attempts to actually treat it are developed in tandem with exploratory work.


#4 Reprogramming ageing

Having removed, replaced and repaired what we can, the final stage in an actual cure for biological ageing will almost certainly require us to reprogram our own biology, hacking what nature has given us to prevent problematic processes from happening in the first place. Since the ‘program’ for our biology is written in our genes, this will involve editing them to optimise the good stuff, reduce the bad and add new capabilities to our cells and organs.

While this might sound futuristic, there’s plenty we can do in the foreseeable future of medical care. It won’t be long before we can use gene editing to optimise the hand that evolution has dealt us, and we could even perform cellular reprogramming – another name for the process of creating induced pluripotent stem cells – to turn back the clock not just in cells in a dish, but our whole bodies.

Upgrading our genes

Our DNA is the blueprint for our bodies, from their large-scale layout to the tiniest components which govern interactions within and between cells. As we discover more about the human genome, there seem to be ever more stories in the press about a ‘gene for’ this or that, and it can be tempting to lapse into ‘genetic determinism’ – believing that your entire biological future, risk of disease, lifespan and even much of your personality, is fixed by the contents of your genetic code.

your lifespan isn’t written in your DNA, and you needn’t see your parents’ longevity as a ceiling on how long you can hope to live. With the right diet, exercise, lifestyle and a bit of luck, our destiny is in our own hands to a larger extent than simplistic genetic determinism would have us believe.

Turning back the epigenetic clock

Exactly how we’ll disentangle the different kinds of epigenetic and other changes which occur during the wide-ranging process of induced pluripotency and transdifferentiation is yet to be seen. There are undoubtedly years of hard scientific graft ahead of us before we fully unpick the details, but

we might see therapies in years or decades rather than centuries

Therapies based on careful use of these reprogramming factors, or clever drugs or other treatments which can mimic their effects, may not be so far away. They may even come sooner than some of the otherwise more straightforward therapies discussed, partly due to the sudden intense interest in therapeutic reprogramming thanks to these promising early results. Using transient reprogramming to turn back the ageing clock is one of the most exciting ideas in biogerontology: it sounds absolutely crazy at first, but the evidence so far suggests it might just work.

Reprogramming biology and curing ageing

Ageing is a phenomenally complex process. Nonetheless, as we’ve seen

we have good ideas as to how we might treat it. All these ideas have, at a minimum, precedent in the lab, and most of them aren’t just speculative treatments based on theory or experiments on cells in a dish.

Once we can model our biology in detail, we will be able to reprogram it to stop the gradual decrease in health and increase in risk of death with time. Human beings will finally be negligibly senescent, biologically immortal – ageless. The treatments that result will bring to an end the huge economic and human cost of natural selection’s negligence, and the pain and suffering in old age which has been an inevitability for most living things for millions of years. It’s a bold mission, but not an unachievable one: human biology is incredibly complex, but it is also finite.

One day, data and powerful computer models will enable us to edit the very code we run on. Reprogramming ageing will be our greatest achievement as a species. It should be our collective mission, as biologists, as doctors and as human beings.


How to live long enough to live even longer

With only a small fraction of life expectancy explained by genes, most of your longevity is down to lifestyle and luck. Luck is, by definition, impossible to do anything about – but there are plenty of scientifically backed suggestions to max out your life expectancy based on how you choose to live.

The advice which will help you live the longest is surprisingly basic in some ways, but it’s also worth saying that following this advice isn’t always easy, and requires both opportunity and willpower. However, now that you know a lot more about the biology of ageing than before, understanding the science behind them will make even familiar suggestions far more compelling.

  1. Don’t smoke

Smoking is outrageously bad for you. If you want to live a long life in good health but you smoke, the first thing you should do is quit.

  1. Don’t eat too much

It won’t come as a surprise that what you eat can have a significant effect on how long you live. Getting a balanced diet with plenty of fruit, vegetables, whole grains and nuts is important and can add substantially to your healthspan and lifespan.

  1. Get some exercise

Exercise is good for your health, and it doesn’t need to be in intimidating amounts: studies show that every minute’s increase in exercise or decrease in time spent inactive per day reduces your risk of death. Exercise is also known to reduce the risk of dozens of diseases, including the most significant age-related ones which you can no doubt reel off by now – it even fends off cognitive decline and dementia.

  1. Get seven to eight hours of sleep a night

Getting seven or eight hours of good-quality sleep per night is probably optimal for health, but it’s hard to be totally sure because sleep is a very tricky thing to study.

Though the evidence isn’t yet totally watertight, getting a good night’s sleep may well improve your healthy lifespan – and make mornings more tolerable as a pleasant side effect.

  1. Get vaccinated and wash your hands

Vaccinations are one of the most important ways that humans have reduced mortality throughout our lives, and getting them doesn’t just protect you, but also those around you. Not only do they mean you’re likely to live longer because you won’t die of whatever infectious disease they prevent, they will also reduce your lifelong burden of inflammation, which can slow ageing, too.

  1. Take care of your teeth

You’ve probably been told one hundred times by your dentist: brush twice a day with fluoride toothpaste, clear out the gaps between your teeth with floss or interdental brushes, and avoid sugary snacks and soft drinks. What you might not know is that your dentist’s advice will affect more than just your smile and future dental bills – it can impact on your lifespan, and even your risk of dementia.

The proposed biological link here is chronic inflammation. The ongoing battle with bacteria in your mouth that cause chronic gum disease, tooth decay and so on, even at low levels, results in a constant fizzing of inflammatory molecules. This, as is now our common refrain, basically accelerates the ageing process.

  1. Wear sunscreen

skin ageing is very closely related to its exposure to the sun. Sun-exposed skin wrinkles more rapidly, is at risk of developing the mottling and discolouration we associate with ageing and, less cosmetically, is at significantly higher risk of transforming into a skin cancer. Getting sunburn just once every two years is associated with increased cancer risk.

  1. Monitor your heart rate and blood pressure

There’s an increasing proliferation of apps and devices to quantify every aspect of your life, but probably the most valuable is the humble automated blood pressure cuff. By measuring your heart rate and blood pressure you can get a significant insight into the state of your cardiovascular health – which, given that heart disease, stroke and vascular dementia are common causes of death and disability, is a significant insight into your health overall.

  1. Don’t bother with supplements

Unless you have a specific vitamin deficiency which you need supplements to treat, the evidence doesn’t support the use of the various vitamin pills on the market.

  1. Don’t bother with longevity drugs – yet

If you have a health condition, medication can literally keep you alive – and it’s obviously best to weigh up the costs and benefits of a particular treatment with your doctor – but, for people who are in generally good health for their age, there’s not yet a pill that can extend your healthy lifespan.

  1. Be a woman

We’ll finish with arguably the least helpful piece of advice: being born a woman can improve your life expectancy by somewhere around five years. There are a variety of social factors which could contribute to this, including more smoking, drinking and risk-taking behaviour in men, as well as more differences in occupations between men and women. However, there are also a few biological explanations for the difference in lifespan between the sexes.