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From Lifespan to Healthspan: What Longevity Research Tells Us (Part 1)

A synthesis of ten papers spanning demography, molecular biology, epigenetics, nutrition, lifestyle science and public health

Lifespan to Healthspan cover image 2

This article is presented in two parts. Part 1 examines the scale of the lifespan-healthspan gap and recent advances in understanding and measuring ageing biology. Part 2 covers proven and emerging interventions, the shift toward personalized healthy-ageing management, and implications for future research and practice.

1. The central problem: we’ve extended life, not health

Research across disciplines converges on the fact that we have extended life, but not health. Life expectancy at birth nearly doubled over the 20th century (47.3 to 78.7 years), but this came mainly from keeping people with disease alive longer, not from delaying disease onset. Disease prevalence has actually risen. The idea of "compression of morbidity" (reduction in unhealthy years before death) remains more aspiration than reality.

 

The same gap shows up in public-health terms: greater life expectancy is often accompanied by more years of ill-health, with rising costs for health and social care, and with the burden distributed unevenly by geography, gender, and socioeconomic status. Neglecting health-span carries real human and economic costs.

2. Is there a hard ceiling on human lifespan?

Absolute gains in life expectancy at very old ages have actually been small. Life expectancy at age 85 rose by just over 1 year across more than a century, even though percentage gains look large. Much of the historical improvement seems to have come from early-life mortality reductions, not from slowing aging itself. This points to modest gains ahead, likely capping out around 95 years for average life expectancy, unless there is a fundamental change in the biology of aging.

 

Other studies argue along similar lines. One proposed a ceiling around 115 years. Another described a mortality "plateau." Both reach a similar conclusion: reliably extending human longevity past 110 years is not currently supported by evidence, though future breakthroughs could change that.

3. The organizing framework: Biology (Hallmarks) of aging

If lifespan gains are capped without advances in biology, the natural next question is: what is the biology of aging, and are there hallmarks we can point to? The Hallmarks of Aging framework, first proposed in 2013 and updated in a 2023 revision, offers some answers. A process qualifies as a "hallmark" only if it (1) manifests with age, (2) accelerates aging when experimentally worsened, and (3) can be therapeutically targeted to slow, halt, or reverse aging.

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The twelve hallmarks fall into three tiers:

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​Primary hallmarks (molecular damage that accumulates with time):

  • Genomic instability — DNA damage accumulates as repair mechanisms falter

  • Telomere attrition — chromosome ends shorten with each cell division

  • Epigenetic alterations — drift in DNA methylation and histone marks

  • Loss of proteostasis — misfolded and damaged proteins accumulate

  • Disabled macroautophagy — the cell’s organelle-recycling system declines 

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Antagonistic hallmarks (helpful in youth, harmful with age — antagonistic pleiotropy):

  • Deregulated nutrient-sensing — the mTOR/AMPK/IGF-1/sirtuin network

  • Mitochondrial dysfunction — declining energy production and rising oxidative stress

  • Cellular senescence — “zombie” cells that stop dividing but secrete inflammatory signals

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Integrative hallmarks (system-level breakdown once damage can no longer be compensated for):

  • Stem cell exhaustion — reduced tissue renewal and repair capacity

  • Altered intercellular communication — degraded hormonal, neural, and immune signaling between cells and organs

  • Chronic inflammation — “inflammaging,” body-wide low-grade immune activation

  • Dysbiosis — age-related disruption of the gut microbiome

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These hallmarks are interconnected. Intervening on one, for example, boosting NAD+ to activate sirtuins shifts several others at once, including DNA repair, autophagy, and mitochondrial quality control. This is why single compounds like metformin, rapamycin, and spermidine show such broad, multi-system effects in the literature.

4. Measuring biological age: the epigenetic clocks

As understanding of the biology of ageing has advanced, researchers have built tools that estimate biological age, using measurable signals like DNA methylation as a proxy. These tools have themselves evolved over time.

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DNAm PhenoAge was the first clock trained to predict health, not just age. It combines 9 blood markers (like glucose, CRP, and white blood cell count) into a score called "Phenotypic Age," then estimates that score from DNA methylation. Because it targets health rather than the calendar, it predicts death, disease, and even Alzheimer's pathology better than earlier clocks. People who score "older" than their real age tend to show more inflammation and less DNA repair activity — a direct link to two other hallmarks: genomic instability and loss of proteostasis

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DNAm GrimAge goes a step further. Instead of one health score, it estimates several disease-linked blood proteins plus a person's lifetime smoking exposure, then combines these into a single number. It outperforms PhenoAge at predicting death, heart disease, and cancer. Notably, its methylation-based smoking estimate predicts mortality better than people's own smoking history — suggesting it captures lasting damage, not just memory of past habits.

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​DunedinPACE takes a different approach: rather than measuring biological age at one point in time, it measures the speed of aging. It was built from two decades of repeated health measurements in the same people, then turned into a single methylation test. Because everyone in the training group was born the same year, the tool cleanly separates aging speed from age itself, and has since been validated in many other studies.

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These clocks are strongly validated for predicting outcomes like death, disease, and physical decline, but their own developers note an open question: whether methylation changes actually drive aging, or simply reflect damage happening elsewhere in the cell, is still unresolved.

Closing of Part 1

Together, these findings show that aging is not just a vague, inevitable decline. It is a set of measurable, connected biological processes. That shift raises the central question of Part 2: what can actually be done about it?

Sources synthesized:

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  1. Crimmins EM. Lifespan and Healthspan: Past, Present, and Promise. Gerontologist. 2015 Dec;55(6):901-11.

  2. Viña J, Borrás C. Unlocking the biochemical secrets of longevity: balancing healthspan and lifespan. FEBS Lett. 2024 Sep;598(17):2135-2144.

  3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278.

  4. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018 Apr 18;10(4):573-591.

  5. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019 Jan 21;11(2):303-327.

  6. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. Elife. 2022 Jan 14;11:e73420.

  7. Pignatti C, D'Adamo S, Stefanelli C, Flamigni F, Cetrullo S. Nutrients and Pathways that Regulate Health Span and Life Span. Geriatrics (Basel). 2020 Nov 19;5(4):95.

  8. Qiu Y, Fernandez-Garcıa B, Lehmann HI, et al. Exercise attenuates the hallmarks of aging: Novel perspectives. J Sport Health Sci. 2026;15:101108.

  9. Liu R, Luo J, Zhang Y, et al. Associations Between Accelerometer-Assessed Sleep Patterns, Proteomic Signatures, and Hallmarks of Aging in Adulthood. Aging Cell. 2026 Sep;25(9):e70685.

  10. Wickramasinghe K, Mathers JC, Wopereis S, Marsman DS, Griffiths JC. From lifespan to healthspan: the role of nutrition in healthy ageing. J Nutr Sci. 2020 Aug 24;9:e33.

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