Longevity Isn't the Finish Line. It's the Last Ten Years.

What you'll learn

Why "how long you live" is the wrong number, and what the better one is

What happened when a demographer audited the Blue Zones records — and how the field answered

Which habits survive that argument regardless of who wins it

The part longevity culture skips: blood pressure, lipids, hearing, teeth

What the industry sells — plasma, supplements, biological-age tests — and what fasting actually does at 16 hours versus ten days

How SmartBar applies the deficiency framework

SmartBar's educational framework begins with two organizing terms, and applies them wherever the body has inputs and burdens — starting with what we can verify in food: ingredient composition, level of processing, and nutritional data. Deficiency means something the body needs and isn't getting. Toxicity means a burden the body must process and clear — not a poison.

Longevity is where the whole framework gets tested, because it's the outcome everything else is supposed to add up to. It's also the topic with the most money in it. This page is educational, not medical advice — and nothing here is a reason to start, stop or change a medication.

Here is the number that should reframe the conversation.

Researchers compared, across 183 World Health Organization member states, how long people live against how long they live in good health. The global gap was 9.6 years, and it had grown 13% since 2000.[1]

Life expectancy rose, but healthy years did not keep pace.

Two details sharpen it. The United States has the largest gap in the analysis — 12.4 years, roughly 29% above the global mean. And women's gap runs 2.4 years wider than men's.[1]

Much of that gap is driven not only by fatal disease but by chronic conditions that erode function for years — including musculoskeletal, neurological, mental-health and genitourinary disorders.[1]

Seneca made the point two thousand years earlier: "It is not that we have a short time to live, but that we waste much of it."

So the question isn't how to reach a bigger number. It's what you'll still be able to do when you get there — walk unaided, rise from a chair, follow a conversation, stay in your own home.

Much of healthy aging is the prevention of frailty — the gradual loss of strength, reserve and resilience that turns ordinary illnesses and falls into life-changing events.[24]

(One measurement note, because this article will hold others to the same standard: health-adjusted life expectancy is a modelled estimate built on disability weights, not a direct measurement of anyone's final decade.)

The famous answer is under serious dispute

If you've heard one longevity story, it's the Blue Zones — regions with extraordinary concentrations of very old people, whose habits were reverse-engineered into advice, a brand, and a documentary series.

Saul Justin Newman, at University College London, reported that extreme-age claims cluster where documentation is poorest. Only 18% of "exhaustively validated" supercentenarians hold a birth certificate — near zero in the United States. Their birthdates cluster on days divisible by five. Introducing state birth certificates was associated with a 69–82% fall in supercentenarian records. In 1997, 30,000 Italians were found claiming pensions while dead.[2] He received the 2024 Ig Nobel Prize in Demography for the work.

Two researchers closely involved in Blue Zones research answered in a peer-reviewed journal. Austad and Pes, writing in The Gerontologist, argue the critique targets the wrong thing: "Blue Zones have never been about the number of supercentenarians, but instead the relative proportion of a population aged 90 or older."[3] Sardinia's designation, they say, rests on cohorts born from 1880 to 1900 being roughly three times likelier to reach 100 than comparison cohorts, supported by civil and church records and complete genealogical reconstruction of six villages.

They also concede something important: Blue Zones are not permanent, and Okinawa no longer qualifies — its defining cohorts were born before 1940, and westernisation has eroded it since.[3]

His paper remains a preprint; theirs is peer-reviewed. Both facts belong in the same sentence.

So the honest position is narrower than either camp's headline. Newman's record-quality challenge is serious and cannot be waved away. The peer-reviewed response describes far more extensive validation than his critique acknowledges — but it comes from researchers closely connected to the work being defended. The dispute is not resolved. What can be said plainly is this: the confidence of the popular lifestyle story greatly exceeds what the demographic evidence can establish — and the package sold from it was never a controlled explanation of longevity.

What survives either way

The habits attributed to those regions are well supported. They never needed the Blue Zones to support them.

Move regularly. Cardiorespiratory fitness is among the strongest measured predictors of survival, with no observed ceiling of benefit across 122,007 treadmill-tested patients.[4]
Build and keep strength. Muscle-strengthening activity is associated with 10–17% lower all-cause mortality at around 30–60 minutes a week.[5]
Eat mostly minimally processed food, with enough protein to hold muscle and enough fibre-rich plants to matter — the argument our Nutrition page makes in full.
Keep people close. Social connection is consistently associated with longer life; isolation with higher mortality.[6]
Have a reason to get up. Purpose is linked to roughly 17% lower mortality across studies of well over 100,000 people.[7]
Sleep on a consistent schedule. In over 60,000 adults tracked by accelerometer, sleep regularity predicted mortality more strongly than duration.[8]
Don't smoke. Quitting before about 45 can eliminate roughly 90% of the excess mortality from continuing.[9]

The advice survives. What's disputed is the story attached to it — that a secret existed, that particular villages held it, and that you could buy it. That distinction matters, because the Blue Zones weren't only a research finding. They were a product. When a real-sounding mechanism gets attached to something sold, the evidence tends to stop keeping up. You'll see that shape repeatedly before this page ends.

The part longevity culture skips

Here is the omission that makes most longevity content useless: it treats the whole subject as behavioural, and quietly ignores ordinary medicine.

Longevity is not only what you do at home. It's also what gets measured early and treated before symptoms appear. Untreated high blood pressure does not care how many supplements you take. Elevated atherogenic cholesterol does not become harmless because a biological-age test improved.

The randomized evidence here is among the largest in medicine. Pooling individual data from roughly 135,000 people across more than twenty trials, each 1.0 mmol/L reduction in LDL cholesterol was associated with major vascular events falling by about a fifth and all-cause mortality by about a tenth.[10] Stated in absolute terms, which matters just as much: in lower-risk people that's roughly 11 fewer major vascular events per 1,000 people over five years.[10]

The physiology — the body makes most of its own — along with the steadily lowered guideline thresholds and the controversies around both, deserves its own article.[11] The point here is narrower: detecting and treating major risk factors is a genuine longevity intervention, and decisions about any individual drug belong with a clinician rather than a website.

Then the parts nobody markets at all.

Hearing. The ACHIEVE trial randomized 977 adults aged 70–84 with untreated hearing loss to hearing intervention or health education. The primary result was null — no reduction in three-year cognitive decline across the whole cohort. But a prespecified analysis found the effect differed by recruitment source: among participants drawn from an existing cardiovascular cohort, who carried higher baseline risk, cognitive decline was 48% slower.[12] The honest reading is null overall, meaningful in those at higher risk — not "hearing aids prevent dementia." Untreated hearing loss can reduce conversation, social participation and cognitive stimulation — all relevant to healthy aging.

Teeth. This sounds trivial until the outcome is defined as functional years. A 2025 systematic review found decreased swallowing function, oral frailty, having fewer than 20 teeth, and edentulism each strongly associated with mortality.[13] Prospective cohorts have also linked worsening oral health with declining physical performance.[13] The plausible chain is the healthspan argument in miniature: oral function affects chewing and food choice; food choice affects nutritional adequacy; and nutrition helps preserve muscle and independence. The observational evidence can't prove each step causes the next — but it shows oral function isn't a cosmetic footnote to aging.

Add vision, sleep apnea treatment, appropriate vaccination and screening, and medication review — and the picture is prevention that includes both refusing unnecessary medicine and using proven medicine before preventable disease removes years of function.

Those are the vital few. The opposite approach is far easier to market.

The most measured self-experiment

Bryan Johnson runs one of the most publicly documented longevity self-experiments in existence, involving extensive testing, numerous daily compounds, prescription drugs and experimental interventions.[14]

The instructive part isn't the extravagance. He discontinued several of the most publicised interventions on his own data — plasma exchange after reporting no measurable benefit, rapamycin after adverse markers, and growth hormone.[14] Publishing negative results and abandoning what appears not to work reflects more scientific discipline than much of the longevity industry.

But Blueprint remains an n=1 experiment with no control group, no randomisation, and too many simultaneous interventions to attribute any result to one cause. A changing biological-age score cannot identify what produced the change.

Rapamycin deserves one separate boundary: it has substantial animal-longevity evidence and legitimate human trials underway, alongside real risks. One person's adverse experience neither proves nor disproves its value.

Before this page goes any further into drugs and procedures: rapamycin, metformin, statins and the rest discussed below are prescription medicines with real risks and real interactions. Nothing on this page is a reason to start, stop or change any of them. Those decisions belong with a prescriber or pharmacist who knows your history, your other medications and your reasons for taking them.

What the industry sells

Young plasma: a regulator has already ruled

Clinics have sold young-donor plasma — reportedly $8,000 a litre — as treatment for aging and cognitive decline. In February 2019 the FDA stated that no clinical benefit had been established for aging or the neurological and cardiovascular conditions being advertised, and that the infusions carried infectious, allergic, respiratory, cardiovascular and fluid-overload risks.[15]

The agency still permits legitimate investigation under an active application. Its objection was not to research, but to selling an unproven treatment. And one of the world's most prominent longevity self-experimenters reported no measurable benefit in himself.

Supplements: one collapse, one open question

Resveratrol is the cautionary tale. Early claims of direct SIRT1 activation depended heavily on artificial assay substrates and were not reproduced with native ones, and convincing human longevity benefit never followed.[16] The supplement remains widely sold.

NAD+ precursors deserve a more open verdict. Nicotinamide riboside raises blood NAD+ in humans, and one small trial in peripheral artery disease improved walking distance — while adding resveratrol produced no further benefit.[17] Large, long-duration trials with longevity-relevant outcomes are still missing. Mechanism and pharmacokinetics are credible; lifespan benefit is unestablished.

Commercial interests exist on both sides of this debate. Check who benefits — including the critics.

Biological-age tests: real science, poor dashboard

Epigenetic clocks are genuine research tools, and several have shown associations with disease risk across populations — although results vary substantially between clocks and studies. That value across populations doesn't make them reliable personal scoreboards.

Different clocks give different answers; results vary with laboratory handling and even time of day; and no model performs best across all outcomes.[18] In the CALERIE trial, two years of calorie restriction modestly changed one pace-of-aging measure while leaving several biological-age estimates unchanged.[18]

Useful for studying populations is not the same as validated for judging whether your protocol worked. The measurement noise may exceed the change you're trying to detect.

Fasting is not one intervention

Time-restricted eating, alternate-day fasting and prolonged fasting get discussed as though they were versions of the same treatment. They aren't.

A 2025 network meta-analysis of 99 randomized trials involving 6,582 adults found that intermittent-fasting strategies and continuous calorie restriction all produced modest weight loss versus unrestricted eating. Alternate-day fasting was the only strategy to outperform continuous restriction — by 1.29 kg, below the authors' own threshold for a clinically important difference, concentrated in shorter trials, and with no superior HbA1c or HDL outcomes.[19]

So intermittent fasting is best understood as an eating structure: useful when a restricted window makes intake easier to control, not demonstrably superior to ordinary restriction over the long term.

Prolonged fasting is different. In 13 adults completing a seven-day fast, maximal strength was maintained — but peak oxygen uptake fell 13%, muscle glycogen halved, and endurance declined.[20] In another supervised study averaging nearly ten days, researchers found several potentially adaptive changes alongside a 129% rise in high-sensitivity CRP and activation of platelet, complement and coagulation pathways — contrary to their own anti-inflammatory hypothesis.[21] Both studies were small. Together they make one point clearly: a multi-day fast is not simply a longer overnight fast.

Human autophagy research has begun, and remains exploratory. One six-month trial found a post-hoc increase in autophagic flux with intermittent time-restricted eating; a small fasting-mimicking trial found an increase with only one of two tested formulations, and involved the product's manufacturer.[22][23] No human evidence establishes that fasting for 16, 18, 24 or any other specific number of hours produces a defined clinical benefit through autophagy.

Nothing in this category has been shown to extend human lifespan. Intermittent fasting may be a practical tool; prolonged fasting remains experimental and introduces medication, electrolyte, dehydration and refeeding risks requiring far greater caution — particularly for anyone pregnant, frail, taking glucose- or blood-pressure-lowering medication, or with a history of disordered eating. A dedicated article will take those distinctions in full.

What actually protects the last ten years

The evidence-backed pattern is now visible: regular movement, strength and balance; minimally processed food with enough protein; consistent sleep; close relationships and purpose; and not smoking. Add the less marketable parts of prevention — knowing your blood pressure, lipids and glucose, and protecting hearing, vision and oral function.

Our Exercise, Sleep, Nutrition and Lifestyle pages take those inputs one at a time, and each starts with the free version.

A more useful personal dashboard than a biological-age score is functional: can you walk at pace, rise from a chair without your hands, carry your shopping, get off the floor, chew a normal meal comfortably, and follow a conversation in a noisy room? Those aren't perfect predictors, but they describe the outcome this article actually cares about — independence.

They're also difficult to commercialise. Nobody can sell you a walk. The interventions with the strongest evidence often have the least marketing behind them, while thin evidence can support an entire company.

And none of this makes longevity entirely earned. Biology, environment, income, accident, infection and access to care write parts of the story nobody chose.

Key Takeaways

The real number is the gap. Globally, 9.6 years are lived in poor health — up 13% since 2000, and largest in the United States.

The Blue Zones demography is genuinely disputed — a preprint against a peer-reviewed reply — but the habits attributed to those regions have independent evidence either way.

Longevity culture skips ordinary medicine. Blood pressure, lipids, glucose, hearing, vision and teeth all shape functional years.

Where a regulator has ruled, it ruled against. The FDA states there is no proven benefit to young-donor plasma for aging.

Biological-age tests are useful in populations, not as personal scoreboards.

Fasting is several different interventions. Intermittent schedules are useful mainly as an eating structure and have not shown meaningful long-term superiority over continuous restriction; prolonged fasting produces deeper physiological changes, carries greater costs, and remains experimental.

How to think about longevity in thirty seconds

Ask what you want to still be able to do at 80, not what number you want to reach.
Spend attention on the vital few — movement, strength, balance, food, sleep, connection, purpose, not smoking.
Get the boring things measured. Blood pressure, lipids, glucose, hearing, vision, teeth. Prevention is not only what you do at home.
Check who benefits. A real mechanism plus a company selling it plus thin outcome data is the most common shape in this field — and it applies to critics too.
Distrust single numbers. Biological age, one hazard ratio, one striking headline. The noise is often larger than the effect.

What SmartBar does with this

SmartBar scores food. It doesn't score your life, estimate your biological age, or tell you how long you'll live — and we'd rather state that boundary than sell a number we can't stand behind.

The app handles one input — food — with every deduction visible, because a score you can't interrogate is just another claim.

That's the same standard this page applies to everything else. The reason the Blue Zones story travelled further than its evidence, the reason resveratrol is still on shelves, and the reason a biological-age number feels like progress is that none of them were built to be checked.

You cannot buy the last ten years. Mostly, you arrive with them already earned — and partly, you arrive with the ones you were given.

This article is educational and is not medical advice. Nothing here is a reason to start, stop or change a prescription medication — rapamycin, metformin, statins and related compounds carry real risks and belong in a conversation with a clinician. Prolonged fasting in particular is not appropriate for many people, including those who are pregnant, frail, taking glucose- or blood-pressure-lowering medication, or with a history of disordered eating. Discuss any significant change with a qualified professional rather than acting on anything read online, including here.

Keep exploring: Lifestyle · Exercise · Sleep · Nutrition · Front-of-package claims

Medical Disclaimer: Read our full Medical Disclaimer

References

Garmany, A., Terzic, A. (2024). "Global Healthspan-Lifespan Gaps Among 183 World Health Organization Member States." JAMA Network Open 7(12):e2450241. DOI: 10.1001/jamanetworkopen.2024.50241. PMCID: PMC11635540. (WHO Global Health Observatory data 2000–2019; mean global gap 9.6 years, +13% since 2000; largest gap in the United States; women's gap 2.4 years wider. Health-adjusted life expectancy is a modelled estimate using disability weights, not direct measurement.)
Newman, S.J. "Supercentenarian and remarkable age records exhibit patterns indicative of clerical errors and pension fraud." bioRxiv 704080. DOI: 10.1101/704080. (Preprint — not peer-reviewed. 18% of validated supercentenarians hold a birth certificate, near zero in the USA; birthdate clustering on days divisible by five; 69–82% decrease in records following introduction of state birth certificates. Awarded the 2024 Ig Nobel Prize in Demography. Newman's earlier peer-reviewed work overturned a 2016 Nature paper on limits to human lifespan.)
Austad, S.N., Pes, G.M. (2025). "The validity of Blue Zones demography: a response to critiques." The Gerontologist 65(12):gnaf246. DOI: 10.1093/geront/gnaf246. PMID: 41405258. (Peer-reviewed reply. States that Blue Zone designation rests on the proportion of a population aged 90 or over rather than supercentenarian counts; describes Level A genealogical validation across six Sardinian villages using civil records from 1866 and church archives; notes Costa Rican vital statistics classified complete by the UN since 1961; and concedes Blue Zones are impermanent, with Okinawa no longer qualifying — its defining cohorts were born before 1940.)
Mandsager, K., et al. (2018). JAMA Network Open 1(6):e183605. DOI: 10.1001/jamanetworkopen.2018.3605. PMID: 30646252. (n=122,007; no observed upper limit of benefit. Observational; clinically referred population.)
Momma, H., et al. (2022). British Journal of Sports Medicine 56(13):755–763. DOI: 10.1136/bjsports-2021-105061. PMID: 35228201. (10–17% lower risk; non-linear dose-response peaking around 30–60 min/week. Observational, self-reported activity.)
Holt-Lunstad, J., et al. (2015). Perspectives on Psychological Science 10(2):227–237. DOI: 10.1177/1745691614568352. PMID: 25910392. See also Holt-Lunstad et al. (2010), PLoS Medicine 7(7):e1000316, and the US Surgeon General's 2023 advisory.
Cohen, R., Bavishi, C., Rozanski, A. (2016). Psychosomatic Medicine 78(2):122–133. DOI: 10.1097/PSY.0000000000000274. PMID: 26630073. (~17% lower all-cause mortality; 10 studies, n=136,265. Observational.)
Windred, D.P., et al. (2024). Sleep 47(1):zsad253. DOI: 10.1093/sleep/zsad253. PMID: 37738616. (60,977 UK Biobank participants; 20–48% lower all-cause mortality across the four more regular quintiles. Observational.)
Le, T.T.T., Mendez, D., Warner, K.E. (2024). American Journal of Preventive Medicine 67(5):684–688. DOI: 10.1016/j.amepre.2024.06.020. PMID: 38936681.
Cholesterol Treatment Trialists' (CTT) Collaboration. Individual participant data meta-analyses of statin trials: Baigent, C., et al. (2005), Lancet 366(9493):1267–1278; CTT Collaboration (2010), Lancet 376(9753):1670–1681, DOI: 10.1016/S0140-6736(10)61350-5; CTT Collaboration (2012), Lancet 380(9841):581–590, DOI: 10.1016/S0140-6736(12)60367-5. (~135,000 participants across >20 trials, median follow-up ~5 years. Per 1.0 mmol/L LDL reduction: major vascular events RR ~0.79 (95% CI 0.77–0.81); all-cause mortality RR 0.90 (0.87–0.93). Absolute effect in lower-risk individuals: approximately 11 fewer major vascular events per 1,000 over five years — relative and absolute figures describe the same result. No evidence of increased cancer incidence or mortality. Note that CTT has been criticised regarding access to individual participant data; that debate belongs to the dedicated cholesterol article.)
Cholesterol physiology and guideline thresholds. Endogenous synthesis and compensation: controlled human metabolic work shows that increased dietary cholesterol intake is compensated for in most people by reduced fractional absorption and/or reduced endogenous synthesis — in the cited work, in 69% of studies — with the degree of compensation varying between individuals — McNamara, D.J., Kolb, R., Parker, T.S., et al. (1987), "Heterogeneity of cholesterol homeostasis in man: response to changes in dietary fat quality and cholesterol quantity," Journal of Clinical Investigation 79(6):1729–1739. DOI: 10.1172/JCI113013. PMID: 3584466. PMCID: PMC424515. Guideline thresholds: Mach, F., Baigent, C., Catapano, A.L., et al. (2020), "2019 ESC/EAS Guidelines for the management of dyslipidaemias," European Heart Journal 41(1):111–188. DOI: 10.1093/eurheartj/ehz455. PMID: 31504418 — lowering the very-high-risk LDL-C goal to below 1.4 mmol/L (55 mg/dL). The body states only the direction of travel; the full physiology and controversies belong to the dedicated cholesterol article.
Lin, F.R., et al. (2023). "Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial." The Lancet 402(10404):786–797. PMID: 37478886. NCT03243422. (n=977, aged 70–84, untreated hearing loss, 3 years. Primary outcome null in the total cohort. Prespecified sensitivity analysis found a significant difference by recruitment source (p-interaction 0.010), with 48% slower cognitive decline among ARIC-cohort participants at higher baseline risk. Secondary analyses report the effect scaling with predicted risk and parallel changes in GFAP and NfL neurodegeneration biomarkers.)
Oral health and function. Systematic review and meta-analysis: "Deteriorated oral health and function as risk factors for physical disability and mortality in community-dwelling older adults" (2025), European Geriatric Medicine. DOI: 10.1007/s41999-025-01319-4. (Adults 50+, searched to February 2025; decreased swallowing function, oral frailty, fewer than 20 teeth, and edentulism strongly associated with mortality. Observational evidence.) Physical function: "Association between oral health markers and decline in muscle strength and physical performance in later life" (2022), The Lancet Healthy Longevity, DOI: 10.1016/S2666-7568(22)00222-7 (two prospective cohorts, UK and USA; tooth loss over follow-up associated with decline in chair stand speed, adjusted OR 2.34 [95% CI 1.20–4.46]; difficulty eating 2.41 [1.04–5.60]).
Bryan Johnson / Project Blueprint. Protocol details — including discontinuation of young-plasma exchange (2023), rapamycin (late 2024) and growth hormone — are drawn from self-published protocol documentation and press coverage rather than peer-reviewed publication. Cited as a documented n=1 self-experiment with no control, no randomisation and no means of attributing change to any single intervention.
U.S. Food and Drug Administration (19 February 2019). "Important Information about Young Donor Plasma Infusions for Profit." FDA Safety and Availability (Biologics) Communication; joint statement of Commissioner Scott Gottlieb and CBER Director Peter Marks. (No proven clinical benefit for aging or the listed conditions; risks include infectious, allergic, respiratory and cardiovascular events and circulatory overload. The FDA explicitly permits investigation under an active Investigational New Drug application.)
Resveratrol and SIRT1 activation. Primary evidence that apparent direct activation of SIRT1 by resveratrol depended on artificial fluorophore-tagged assay substrates and was not reproduced with native peptide substrates: Kaeberlein, M., McDonagh, T., Heltweg, B., et al. (2005), "Substrate-specific activation of sirtuins by resveratrol," Journal of Biological Chemistry 280(17):17038–17045, DOI: 10.1074/jbc.M500655200, PMID: 15684413; Borra, M.T., Smith, B.C., Denu, J.M. (2005), "Mechanism of human SIRT1 activation by resveratrol," Journal of Biological Chemistry 280(17):17187–17195, DOI: 10.1074/jbc.M501250200, PMID: 15749705. (The body claim is deliberately limited to the substrate-artifact finding and the absence of convincing human longevity benefit. The wider history — invertebrate lifespan findings attenuating under controlled genetic background, subsequent retractions in the sirtuin literature, and the closure of the commercial programme built on the mechanism — is real but is not asserted in the body, because each element would need its own primary notice.)
McDermott, M.M., Martens, C.R., Domanchuk, K.J., et al. (2024). "Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial." Nature Communications 15:5046. DOI: 10.1038/s41467-024-49092-5. PMID: 38871717. NCT03743636. (n=90; six months of nicotinamide riboside improved six-minute walk distance versus placebo; adding resveratrol produced no benefit over NR alone. The trial used a prespecified one-sided significance level of 0.10, a further reason for restrained interpretation, and the authors note a confirmatory trial is needed. Disclosure: study supplements were supplied by ChromaDex and ReserveAge. Human NAD+ elevation from oral NR established by Trammell et al. (2016), Nature Communications.)
Epigenetic clocks. Sehgal, R., Borrus, D., Gonzalez, J., Markov, Y., ADNI, Higgins-Chen, A. (2025). "Biological versus Technical Reliability of Epigenetic Clocks and Implications for Disease Prognosis and Intervention Response." bioRxiv 2025.10.13.682176. DOI: 10.1101/2025.10.13.682176 (preprint; 18 clocks; excellent technical reproducibility, biological reliability a critical limitation, with drops related to slide position and DNA extraction). Diurnal variation: Koncevičius, K., et al. (2024), "Epigenetic age oscillates during the day," Aging Cell 23:e14170. Heterogeneity: Mavrommatis, C., Belsky, D.W., Ying, K., et al. (2025), "An unbiased comparison of 14 epigenetic clocks in relation to 174 incident disease outcomes," Nature Communications 16:11164, DOI: 10.1038/s41467-025-66106-y (14 clocks, 174 incident outcomes, 18,859 people; no clear best clock across diseases, later-generation clocks generally outperforming first-generation ones). Predictive validity: "Accelerated biological aging based on DNA methylation clocks is a predictor of stroke occurrence: a systematic review and meta-analysis" (2025), Frontiers in Neurology, DOI: 10.3389/fneur.2025.1640853 (13 studies; OR 1.16 — but with extremely high heterogeneity, I² = 98.9%, materially limiting what the pooled estimate means). Intervention response: Waziry, R., Ryan, C.P., Corcoran, D.L., et al. (2023), "Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial," Nature Aging 3(3):248–257, DOI: 10.1038/s43587-022-00357-y — an effect on DunedinPACE without significant change in PhenoAge or GrimAge.
Semnani-Azad, Z., Khan, T.A., Chiavaroli, L., et al. (2025). "Intermittent fasting strategies and their effects on body weight and other cardiometabolic risk factors: systematic review and network meta-analysis of randomised clinical trials." BMJ 389:e082007. DOI: 10.1136/bmj-2024-082007. PMID: 40533200. PMCID: PMC12175170. (99 RCTs, 6,582 adults, median age 45, median BMI 31.3, 66% female, trials 3–52 weeks, GRADE-assessed. All strategies reduced weight versus unrestricted diets; alternate-day fasting the only strategy to beat continuous energy restriction, by 1.29 kg — below the authors' own 2.0 kg minimally important difference, and mainly in trials under 24 weeks. No benefit for HbA1c or HDL in any strategy. Funding disclosure: an author reports research support from the International Life Sciences Institute and the National Honey Board.)
Kolnes, K.J., Nilsen, E.T.F., Brufladt, S., et al. (2025). "Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans." Nature Communications 16:122. DOI: 10.1038/s41467-024-55418-0. PMCID: PMC11695724. (13 participants, 7 male and 6 female; 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass lost; maximal isometric and isokinetic strength unchanged; peak oxygen uptake decreased 13%; muscle glycogen halved; PDK4 expression increased 13-fold with reduced carbohydrate oxidation and decreased endurance capacity. Measured lean mass includes water and glycogen-associated mass. Small sample.)
Commissati, S., Lastra Cagigas, M., Masedunskas, A., et al. (2025). "Prolonged fasting promotes systemic inflammation and platelet activation in humans: A medically supervised, water-only fasting and refeeding study." Molecular Metabolism 96:102152. DOI: 10.1016/j.molmet.2025.102152. PMID: 40268190. (20 volunteers, mean age 52.2, mean fast 9.8 ± 3.1 days plus 5.3 ± 2.4 days guided refeeding. Adaptations included preserved skeletal muscle and bone signals, enhanced lysosomal biogenesis and reduced circulating Aβ40/Aβ42. Contrary to the authors' hypothesis, hsCRP rose 129%, with platelet degranulation and complement/coagulation upregulation; a retrospective cohort of 1,422 individuals confirmed increased CRP. Levels returned to baseline after refeeding in all but one participant. Authors describe the response as potentially adaptive while raising concern about cardiometabolic effects persisting after refeeding.)
Bensalem, J., et al. (2025). "Intermittent time-restricted eating may increase autophagic flux in humans: an exploratory analysis." The Journal of Physiology 603(10):3019–3032. DOI: 10.1113/JP287938. PMID: 40345145. (121 adults with obesity randomized to standard care, calorie restriction, or intermittent fasting plus time-restricted eating for 6 months; autophagic flux measured as LC3B-II flux in peripheral blood mononuclear cells. No significant between-group difference at 2 months; significant difference for iTRE versus standard care at 6 months, P = 0.04, post hoc, with the authors noting the effect may be partly driven by autophagy decreasing in the control group. Calorie restriction versus standard care not significant. Exploratory.)
"Effect of fasting-mimicking diet on markers of autophagy and metabolic health in human subjects" (2025). GeroScience. DOI: 10.1007/s11357-025-02035-4. (Published online December 2025. Pilot randomized trial, 30 healthy participants, two FMD formulations or control over 8 days; increased autophagic flux observed in one of the two formulations, with effects not consistent across all time points. Conducted in collaboration with the commercial manufacturer of the tested product, and the author list includes company employees — disclosed on the principle applied throughout this library.)
Clegg, A., Young, J., Iliffe, S., Olde Rikkert, M., Rockwood, K. (2013). "Frailty in elderly people." The Lancet 381(9868):752–762. DOI: 10.1016/S0140-6736(12)62167-9. PMID: 23395245. (Frailty as a state of vulnerability to poor resolution of homoeostasis after a stressor event, arising from cumulative decline across multiple physiological systems, with reserves depleting until minor stressors trigger disproportionate changes in health status. Review article. Appears out of numerical sequence relative to first mention — normalise reference order at final copyedit.)

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