24.8 — Ageing, and What Genuinely Extends a Life

Jeanne Calment died in 1997 at 122 years and 164 days, the longest confirmed human lifespan.

She met Vincent van Gogh. She sold canvases in her uncle's shop in Arles as a teenager, and described him as dirty and disagreeable.

She took up fencing at 85, rode a bicycle until 100, and smoked until she was 117.

Which is exactly the kind of anecdote that teaches nothing — one person's genetics tells you nothing about your own, and the smoking is noise rather than signal.

What does teach something is the gap between two numbers: life expectancy and healthy life expectancy.

Global life expectancy is around 73 years. Healthy life expectancy — years lived in good health — is around 63.

Which means roughly a decade at the end spent in poor health.

And nearly everything that works to extend life also compresses that gap. The goal is not more years of decline. It is the same span of decline pushed later, which is what the evidence actually supports.

What ageing is

Not one process. Several, running in parallel, and they are now reasonably well characterised.

The hallmarks of ageing, as they are usually grouped:

Genomic instability — DNA damage accumulating faster than repair can manage.

Telomere shortening — the protective caps on chromosome ends shorten with each division (Chapter 2.2). When they become critically short, the cell stops dividing. This is a real mechanism, and the popular idea that lengthening telomeres would extend life is complicated by the fact that cancer cells do exactly that.

Epigenetic changes — the pattern of chemical marks controlling which genes are switched on drifts with age (Chapter 2.4). And this drift is measurable enough to build epigenetic clocks that estimate biological age, sometimes more accurately than the calendar does.

Loss of protein quality control — misfolded proteins accumulating, which underlies Alzheimer's and Parkinson's (Chapters 20.3, 20.4).

Deregulated nutrient sensing — the insulin, IGF-1 and mTOR pathways, which are the ones most implicated in the lifespan effects of diet.

Mitochondrial dysfunction — less efficient energy production (Chapter 1.6).

Cellular senescence — cells that stop dividing but do not die, and instead secrete inflammatory signals. They accumulate with age and drive tissue dysfunction, which makes them a major research target.

Stem cell exhaustion — reduced capacity for tissue renewal.

Altered intercellular communication — including chronic low-grade inflammation, sometimes called inflammaging.

Plus, in more recent versions: chronic inflammation, and changes in the gut microbiome.

And a useful frame: ageing is the accumulation of damage plus the failure of the systems that repair it.

What changes, system by system

Heart and vessels — arteries stiffen, so systolic blood pressure rises; maximum heart rate falls by roughly one beat per year.

Lungs — elastic recoil falls, chest wall stiffens, and vital capacity declines.

Muscle — sarcopenia: 3 to 8 percent loss per decade after 30, accelerating after 60, with power lost fastest (Chapter 24.6).

Bone — density falls, particularly rapidly in women after menopause (Chapter 21.6).

Brain — modest volume loss; processing speed slows; and crystallised intelligence — knowledge and vocabulary — is preserved or improves into old age, while fluid intelligence and processing speed decline. Which is why an older person is slower at a novel puzzle and better at judgement.

Kidneys — filtration rate falls by around 1 percent a year after 40, which is why drug doses change (Chapter 21.3).

Immune system — immunosenescence: weaker responses to new pathogens and to vaccines, with more chronic background inflammation.

Senses — presbyopia from around 40, high-frequency hearing loss, and reduced taste and smell.

Skin — thinner, less elastic, slower to heal.

Hormones — menopause in women (Chapter 15.10); a gradual decline in testosterone in men; reduced growth hormone.

What genuinely extends life

And this is the section that matters, because the list is short, unglamorous and extremely well supported.

1. Do not smoke

The single largest modifiable factor.

Smoking costs around 10 years of life expectancy on average.

Quitting at 30 avoids almost all of it. Quitting at 40, 50 or 60 gains roughly 9, 6 and 3 years respectively.

Quitting at any age is worth doing (Chapter 20.10).

2. Stay physically active

Around 30 percent lower all-cause mortality (Chapter 24.5).

And cardiorespiratory fitness is one of the strongest predictors of mortality that has been measured — stronger in several analyses than smoking, diabetes or hypertension.

With strength and balance training becoming more important with age, not less.

3. Eat well

Around 20 to 30 percent lower cardiovascular mortality with a Mediterranean-style pattern (Chapter 24.4).

4. Maintain a healthy weight

Obesity reduces life expectancy, with the effect rising steeply at higher BMIs.

And a nuance worth including: in older adults, being slightly above the "normal" range is not associated with harm, and being underweight is associated with worse outcomes — because muscle mass and reserve matter more at that age than the number does.

5. Limit alcohol

No level is established as beneficial, and risk rises with intake (Chapter 24.1).

6. Sleep 7 to 9 hours

Both short and long sleep are associated with higher mortality, with short sleep more clearly causal (Chapter 24.7).

7. Stay socially connected

And this is the one people are most surprised by.

A meta-analysis covering over 300,000 people found that strong social relationships were associated with a 50 percent increased likelihood of survival — an effect comparable to quitting smoking and larger than obesity or physical inactivity.

Loneliness is associated with increased cardiovascular disease, dementia and mortality.

Which makes social connection a health intervention rather than a lifestyle preference, and it is one of the few areas where the effect size genuinely rivals the big medical ones.

8. Have a sense of purpose

Consistently associated with lower mortality and better health across multiple large cohorts.

The Japanese concept of ikigai — a reason to get up in the morning — captures it, and the association survives adjustment for the obvious confounders.

9. Manage blood pressure, cholesterol and glucose

These are the three numbers that quietly determine cardiovascular outcomes (Chapter 18.1), and treating them works.

10. Take the vaccines and the screening

Influenza, pneumococcal, shingles, COVID and RSV vaccines in later life reduce serious illness and death (Chapter 13.5).

And screening that has evidence: bowel, breast and cervical cancer, abdominal aortic aneurysm in men, and blood pressure.

11. Protect your hearing and vision

Untreated hearing loss is the largest single modifiable dementia risk factor (Chapter 20.4), and it drives isolation.

Both are correctable, and both are neglected.

12. Prevent falls

Because a hip fracture at 80 changes the rest of a life (Chapter 21.6).

Strength and balance training, medication review, vision correction, and home safety.

The things people ask about

Caloric restriction

Extends lifespan in yeast, worms, flies and rodents — reliably and substantially.

In primates, two long studies reached different conclusions, with the discrepancy largely explained by what the control animals were fed.

In humans, the CALERIE trial achieved around 12 percent calorie restriction over two years and produced improvements in cardiometabolic risk markers. Lifespan cannot be tested in a human trial for obvious reasons.

The honest position: it improves health markers, the effect on human lifespan is unknown, and sustained severe restriction carries real costs — bone loss, muscle loss, cold intolerance, reduced libido and preoccupation with food.

Fasting

Intermittent fasting and time-restricted eating produce benefits largely attributable to reduced calorie intake (Chapter 24.4).

Autophagy — the cell's process of clearing damaged components — is upregulated by fasting, and the extrapolation from that to specific human longevity benefits runs ahead of the evidence.

The supplements

And this is where the gap between enthusiasm and evidence is widest.

Metformin — observational data suggested people with diabetes on metformin had unexpectedly good outcomes. The TAME trial, designed to test it as an anti-ageing drug, has struggled for funding. Interesting, unproven.

Rapamycin — extends lifespan in mice reliably, including when started in mid-life, by inhibiting mTOR. Immunosuppressive at the doses used in transplantation. Under investigation in humans at intermittent low doses. Not established.

NAD+ precursors — nicotinamide riboside, NMN. NAD+ falls with age, and restoring it helps in mice. Human trials so far show it raises NAD+ levels and have not shown clear clinical benefit.

Resveratrol — the red wine compound. Early findings did not replicate, and enthusiasm has faded considerably.

Senolytics — drugs that clear senescent cells. Genuinely promising in animal models, with early human trials underway. Not ready.

Collagen supplements — some evidence for skin and joint outcomes, and mechanistically odd, since collagen is digested into amino acids like any other protein.

Antioxidant supplements — repeatedly failed, and some increased mortality (Chapter 24.2).

The honest summary: no supplement has been shown to extend human lifespan. The field is genuinely interesting and moving, and anyone selling you a longevity product today is ahead of the evidence.

Blood tests and biological age

Epigenetic clocks estimate biological age from DNA methylation patterns and are a real research tool.

The consumer versions vary in quality, are not standardised, and it is not established that acting on the result changes anything.

Interesting. Not yet actionable.

What actually happens at the end

And this belongs in an honest chapter about ageing.

Most people in high-income countries now die of chronic disease after a period of decline, rather than suddenly.

Which makes advance planning valuable, and it is consistently deferred (Chapter 20.4).

Worth doing while well:

An advance decision recording what treatment you would refuse.

A lasting power of attorney for health and welfare, naming someone to decide if you cannot.

A conversation with your family about what matters to you — which is the part that makes the documents work, because relatives who have had the conversation make decisions with far less distress than those handed a form.

And knowing what palliative care actually is, because it is widely misunderstood.

It is specialist symptom control and support, and it can run alongside active treatment rather than replacing it.

A landmark trial in advanced lung cancer found that patients receiving early palliative care alongside standard treatment had better quality of life, less depression — and lived longer.

Which is worth stating plainly: comfort-focused care is not giving up, and in that study it was associated with living longer, not shorter.

The realistic picture

Around 25 percent of the variation in human lifespan is genetic. The rest is environment, behaviour and luck.

Which is more encouraging than it sounds, because it means most of it is not decided in advance.

And the most useful reframing in the whole field is the compression of morbidity.

The goal is not to extend the years of decline. It is to stay healthy for longer and compress the period of illness into a shorter span at the end.

Everything on the list above does that. People who exercise, do not smoke, eat well and stay connected do not merely live longer — they spend fewer of their years disabled.

The person still walking, still lifting things, still going out and still seeing friends at 85 is not lucky. In the great majority of cases they are the product of decades of ordinary decisions, none of which felt decisive at the time.

None of it requires a supplement, a clinic or a protocol.

Move. Eat real food. Sleep. Do not smoke. Keep your people close. Have something to get up for. And treat the numbers your doctor measures.

That is the whole of it, and it is the best-supported advice in medicine.

What the next page fixes

Chapter 24.9 closes the volume with something small and genuinely useful — how expiry dates are actually calculated, and what they do and do not tell you.