Biomarkers of Ageing

A biomarker of ageing is a measurable parameter reflecting biological age rather than chronological age, which predicts adverse outcomes in late life.

The rationale is the geroscience hypothesis — accumulation of diseases and loss of function is driven by common biological mechanisms. Measuring these allows prediction of outcomes and testing of interventions that extend healthspan.

Chronological age is only a surrogate marker — it stands in for the specific impairments that actually increase vulnerability.

The core problem: there is no agreed definition of what a biomarker of ageing should measure or predict. This is the biggest obstacle in the field.

Death alone is an insufficient outcome, because death is often preceded by years of multimorbidity and disability.

Three outcomes currently anchor biomarkers: age-related multimorbidity, frailty, and intrinsic capacity.

Epigenetic clocks (DNA methylation age) — methylation status of CpG islets predicts donor age with average error <5 years (Hannum, Horvath).

The gap between methylation age and chronological age is associated with cognitive and physical function, frailty and age-related diseases, and is an independent predictor of all-cause mortality. These are the best-validated molecular markers.

Telomere length is NOT currently accepted as a biological age marker. A meta-analysis of 25 studies showed telomere attrition predicts all-cause mortality, but longitudinal changes are erratic, probably due to measurement error.

Genomic instability — somatic mutations, translocations, aneuploidy. Robust evidence linking mutation burden to human ageing phenotypes is still lacking.

Cellular senescence — p16INK4a is the key marker. It correlates with age in human skin, and p16INK4a-positive cell burden in thigh adipose tissue correlates with muscle strength and walking performance.

In a meta-analysis of 372 GWAS, the ink4/ark locus was linked to the greatest number of age-associated diseases — Alzheimer's, cardiovascular disease, cancer and type 2 diabetes.

SASP — matrix metalloproteases and pro-inflammatory cytokines released by senescent cells; a measurable output of senescence.

Mitochondrial function can now be measured in vivo and is associated with muscle strength and mobility. Powerful but needs standardisation.

Proteostasis and autophagy — autophagy is better maintained in offspring of exceptionally long-lived individuals.

Metabolic markers — insulin resistance, increased visceral fat with reduced skeletal muscle mass, and decline in sex steroids, GH and IGF-1. Reduced insulin/IGF-1/mTOR signalling is associated with longevity.

Inflammageing and immunosenescence — raised IL-6, raised CRP, reduced IL-2 and IL-2 responsiveness, thymic atrophy, fewer naive T cells with inflation of memory T cells, and shrinkage of the antigenic repertoire (Table 2.3). Plasma IL-6 rises with normal ageing and correlates inversely with functional ability.

Stem cell exhaustion is conceptually important but difficult to measure before its clinical consequences appear.

Physical function is the proposed clinical biomarker of healthy ageing — aerobic capacity, gait speed, balance, mobility, muscle strength. It predicts adverse events, disability and mortality.

Gait speed predicts mortality in older adults better than chronic diseases such as hypertension, and takes no longer to measure than a routine vital sign.

Grip strength — EWGSOP2 cut-offs for low strength are <27 kg in men and <16 kg in women; low appendicular muscle mass is <20 kg (men) and <15 kg (women).

Short Physical Performance Battery (SPPB) — 4-metre walk + repeated chair stands + balance; predicts future disability, hospitalisation and mortality.

Frailty is the clinical metric of biological ageing. Frail patients show higher factor VIII, D-dimer, CRP, leukocytes, fibrinogen and glucose, with low vitamin D and low haemoglobin.

Intrinsic capacity (WHO) — the composite of all physical and mental capacities (cognition, psychological, sensory, locomotion, vitality) — is the key determinant of functional ability.

A formal validation framework now exists. The Biomarkers of Aging Consortium published recommendations on how biomarkers of ageing must be validated before clinical translation, noting that systematic validation is what will accelerate their use in gerotherapeutic trials. The stated problem was that although omics-based biomarkers could serve as surrogate endpoints, no consensus existed on validation. A joint NIA–Consortium symposium in 2024 emphasised understanding the longitudinal, complex and heterogeneous nature of ageing. (Nature Medicine 2024)

Organ-specific ageing clocks. Ageing is no longer one number for the whole body. Plasma proteomic signatures of organ ageing track health and disease; brain and immune ageing predict healthspan and longevity; organ-specific signatures predict 20-year risk of age-related diseases. Clinical meaning: a patient may have a "young heart" but an "old brain", allowing organ-targeted prevention. (Nature 2023; Nat Med 2025; Lancet Digit Health 2025)

Third-generation clocks measure pace, not level. DunedinPACE measures the pace of ageing and is sensitive to short-term change and intervention; DunedinPACNI estimates pace from a single brain MRI. In the Framingham Offspring cohort, faster DunedinPACE was associated with worse global cognition and steeper cognitive decline after adjusting for education. (Trends Mol Med 2025; Nat Aging 2025)

GDF-15 — the most promising single blood biomarker in geriatrics. In the longitudinal FRASNET study, higher baseline GDF-15 prospectively identified individuals at high risk of developing frailty (AUC 0.85–0.96), malnutrition (AUC 0.94) and falls (AUC 0.98) over six years. In LIFE, GDF-15 showed one of the strongest associations with slower walking speed. BIOFRAIL evaluated plasma GDF-15 in 429 mobility-limited older adults (mean age 79.6) against CFS ≥5 and EWGSOP2 sarcopenia. Mechanism: GDF-15 reflects mitochondrial dysfunction and inflammageing via AMPK signalling. (GeroScience 2025; Ageing Res Rev 2026)

Organ-specific consensus frameworks. The Aging Biomarker Consortium now defines biomarker panels organ by organ — cardiac ageing, vascular ageing, visual system ageing and adipose tissue ageing — each providing a multi-dimensional framework covering functional, morphological and molecular biomarkers. (Life Medicine 2023–2025)