Horvath Lab Biology of Aging and Epigenetic Clocks

Themes in the Horvath Lab

Longevity biomedicine has no shortage of candidate interventions. What it lacks is a trustworthy way to tell which of them actually move human aging. That is the problem this lab works on, and increasingly we intend to be among the people moving it.

Every theme below either builds a trustworthy readout of aging, gets one recognized, or applies one to decide who to treat and whether a treatment worked.

The order is an argument. We start with what we want to achieve, then the analysis that tells us where to aim, then the measurement discipline that decides whether we hit anything, then the comparative work that tells us whether a finding generalizes, and finally the human populations, above all those living with chronic infection, where aging is visibly accelerated and the experiment is already running.

Interventions that restore a youthful epigenome

If the epigenome records age, the question that follows is whether a youthful state can be restored, safely and durably, in a living person. We are interested in interventions that restore youthful epigenetic state: gene therapies that act on the epigenome, and small molecules that act on the machinery which establishes and maintains epigenetic marks. We are as interested in the interventions that fail, and in understanding why they fail, as in the ones that work.

Gene-therapy approaches directed at the epigenome; pharmacological modulation of the enzymes that maintain epigenetic state; retrotransposon and inflammatory axes as points of intervention. Where we intervene is chosen from our causal analyses. The intervention platforms come through collaboration with academic laboratories, contract research organizations and clinical groups, and our own contribution is the readout that decides whether an intervention worked.

Ambition. Move from restoring a youthful epigenetic state to showing that doing so restores function.

Selected papers

  1. Fahy GM, Brooke RT, … Horvath S. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 2019.
  2. Horvath S, Singh K, … Katcher HL. Reversal of biological age in multiple rat organs by young porcine plasma fraction. GeroScience 2023.
  3. Horvath S, Lu AT, Cohen H, Raj K. Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation. Aging 2019.
  4. Horvath S, Zoller JA, … Salmon AB. DNA methylation age analysis of rapamycin in common marmosets. GeroScience 2021.
  5. Bischoff-Ferrari HA, … Horvath S. Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial. Nature Aging 2025.
  6. Zhang B, … Horvath S, Gladyshev VN, White JP. Multi-omic rejuvenation and lifespan extension on exposure to youthful circulation. Nature Aging 2023.

Causal epigenetic clocks: drivers, not passengers

Epigenetic clocks read chemical marks on DNA and estimate biological age with real accuracy. But accuracy is not mechanism. Most of the sites a clock reads are consequences of aging rather than causes of it, and a clock built on consequences can be moved without touching the biology underneath, so that the marker improves while the person does not. We build clocks whose constituent sites have passed a causal test, so that moving the clock means moving the biology.

Mendelian randomization, colocalization and perturbation evidence to separate causal CpGs from correlated passengers; pathway- and module-specific clocks anchored to defined aging processes such as inflammation, DNA repair, Polycomb-target methylation and enhancer function, rather than to chronological age alone; and explicit evidence ladders that state what "causal" is being claimed at each rung, and what it is not.

Ambition. A clock a rejuvenation trial can trust, because its parts are drivers.

Selected papers

  1. Ying K, … Horvath S, … Gladyshev VN. Causality-enriched epigenetic age uncouples damage and adaptation. Nature Aging 2024.
  2. Morales Berstein F, … Horvath S, … Richmond RC. Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study. eLife 2022.
  3. McCartney DL, … Horvath S, Marioni RE. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging. Genome Biology 2021.
  4. Lu AT, … Horvath S. GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nature Communications 2018.
  5. Moqri M, … Horvath S, Snyder MP, Sebastiano V. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation. Nature Communications 2024.
  6. Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics 2018.

Biological age as a measurement you can act on

A biomarker becomes useful only when it is reproducible enough that a change in it means something. Much of the published criticism of epigenetic clocks is really criticism of measurement precision, and some of it is fair. We work on the unglamorous half of the field: how reliably biological age can be measured, how large a change has to be before it can be distinguished from noise, and what it would take for a clinician, a trialist or a regulator to treat that change as evidence rather than as a suggestion.

Variance decomposition into technical and biological components; intraclass correlation and minimal detectable change set against realistic intervention effect sizes; head-to-head benchmarking across measurement platforms; surrogate-endpoint statistics, including mediation and meta-analytic surrogacy; and the regulatory frameworks under which a molecular measure of aging could be qualified for a narrowly defined context of use.

Ambition. Help develop molecular measures of aging robust enough to serve as recognized endpoints in clinical research. This is a long project and a collective one, and we would rather build it with well-resourced partners than alone.

Selected papers

  1. Moqri M, … Horvath S, Ferrucci L. Validation of biomarkers of aging. Nature Medicine 2024.
  2. Moqri M, … Horvath S, … Gladyshev VN. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell 2023.
  3. Biomarkers of Aging Consortium, … Horvath S, … Gladyshev VN. Challenges and recommendations for the translation of biomarkers of aging. Nature Aging 2024.
  4. Bell CG, … Horvath S, … Rakyan VK. DNA methylation aging clocks: challenges and recommendations. Genome Biology 2019.
  5. Gorelov R, … Horvath S, Hochedlinger K. Dissecting the impact of differentiation stage, replicative history, and cell type composition on epigenetic clocks. Stem Cell Reports 2024.
  6. Horvath S, Topol EJ. Digitising the ageing process with epigenetic clocks. The Lancet 2024.

Comparative and multi-omic readouts of aging

Aging is not written only in DNA methylation, and not only in humans. Species whose lifespans differ by orders of magnitude, among them mice, bats, whales and humans, share far more of their aging signature than anyone expected. We build measurements that hold across species, across tissues, and across molecular layers, on the reasoning that a signal surviving all three is much more likely to reflect something real about aging than one tuned to a single dataset.

Cross-species methylation platforms and universal clocks; extension of aging readouts beyond DNA methylation into other molecular layers of the epigenome and adjacent omics; cell-type-resolved and single-cell estimation, including deconvolution that separates genuine epigenetic change from shifting cell composition; and long-read sequencing for allele-resolved methylation and for repeat-element regions that arrays cover poorly. Methods and software are released openly.

Ambition. Readouts of aging that generalize across species, tissues, single cells and molecular layers, rather than one more predictor of chronological age.

Selected papers

  1. Lu AT, Fei Z, Haghani A, et al., Horvath S. Universal DNA methylation age across mammalian tissues. Nature Aging 2023.
  2. Haghani A, Li CZ, … Horvath S. DNA methylation networks underlying mammalian traits. Science 2023.
  3. Li CZ, … Horvath S. Epigenetic predictors of species maximum life span and other life-history traits in mammals. Science Advances 2024.
  4. Horvath S, Zhang J, Haghani A, Lu AT, Fei Z. Fundamental equations linking methylation dynamics to maximum lifespan in mammals. Nature Communications 2024.
  5. Arneson A, … Ernst J, Horvath S. A mammalian methylation array for profiling methylation levels at conserved sequences. Nature Communications 2022.
  6. Horvath S. DNA methylation age of human tissues and cell types. Genome Biology 2013.
  7. de Lima Camillo LP, Asif MH, Horvath S, Larschan E, Singh R. Histone mark age of human tissues and cell types. Science Advances 2025.

Infection, immunity, and accelerated aging

Some people age faster than their birthdays suggest, and chronic viral infection is among the clearest reasons why. People living with HIV show accelerated epigenetic aging even when the virus is well controlled. That makes chronic infection both a window onto what actually drives biological aging and an unusually practical place to intervene, because the relevant drugs and vaccines are already approved, already inexpensive, and already taken by millions of people. We study how persistent viruses accelerate the epigenetic clock, and whether the treatments that control them, and the vaccines that prevent them, slow it back down.

Epigenetic age acceleration in chronic viral infection, with HIV as the primary model and other persistent viruses as extensions; repurposing of antiretroviral therapy, in particular nucleoside reverse-transcriptase inhibitors, which act on the retrotransposon and interferon axes implicated in inflammatory aging; longitudinal within-person designs in treated cohorts rather than cross-sectional comparisons; and the emerging observational evidence that vaccination against herpes zoster tracks with slower epigenetic aging and lower dementia incidence, a convergence we regard as important, causally unsettled, and testable.

Ambition. Determine whether controlling chronic infection is among the cheapest available levers on human biological age, and if it is, identify which of the drugs and vaccines already on the shelf actually pull it.

Selected papers

  1. Horvath S, Levine AJ. HIV-1 Infection Accelerates Age According to the Epigenetic Clock. The Journal of Infectious Diseases 2015.
  2. Horvath S, Lin DTS, … Levine AJ. HIV, pathology and epigenetic age acceleration in different human tissues. GeroScience 2022.
  3. Horvath S, Phillips N, … Hoare J. Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS 2018.
  4. Breen EC, Sehl ME, … Horvath S, … Jamieson BD. Accelerated aging with HIV occurs at the time of initial HIV infection. iScience 2022.
  5. Sehl ME, … Horvath S, … Jamieson BD. The effects of anti-retroviral therapy on epigenetic age acceleration observed in HIV-1-infected adults. Pathogens and Immunity 2020.
  6. Schaenman J, … Horvath S, Elashoff D. DNA methylation age is more closely associated with infection risk than chronological age in kidney transplant recipients. Transplantation Direct 2020.