Hallmarks of Aging
A navigational MOC (map of content) over the 12 hallmarks defined by LĂłpez-OtĂn, Blasco, Partridge, Serrano, and Kroemer (2013, expanded 2023). The original 2013 paper defined 9 hallmarks; the 2023 update added 3 more.
A hallmark of aging should ideally fulfill three criteria: (1) manifest during normal aging; (2) experimental aggravation accelerates aging; (3) experimental amelioration retards aging and increases healthspan.
— LĂłpez-OtĂn et al. 2013
This page is a navigational overlay — facts live on the per-hallmark pages in hallmarks/.
A note on what’s verified
Both source papers are verified against the full PDFs as of 2026-05-04:
- lopez-otin-2013-hallmarks-of-aging — full text at doi.org/10.1016/j.cell.2013.05.039
- lopez-otin-2023-hallmarks-expanding-universe — full text at doi.org/10.1016/j.cell.2022.11.001
All 12 hallmarks, the Primary/Antagonistic/Integrative categorization, and the causal-cascade hypothesis (Primary triggers → Antagonistic responses → Integrative outcomes) are confirmed against the source figures. The 2023 paper additionally introduces a “strata of organismal organization” overlay (Figure 7) mapping each hallmark to a level from molecules → meta-organism — this is a complementary axis not yet integrated into this MOC.
Primary hallmarks (causes of damage)
These are the upstream causes of cellular damage; their effects accumulate progressively.
| Hallmark | Page | Introduced |
|---|---|---|
| Genomic instability | genomic-instability | 2013 |
| Telomere attrition | telomere-attrition | 2013 |
| Epigenetic alterations | epigenetic-alterations | 2013 |
| Loss of proteostasis | loss-of-proteostasis | 2013 |
| Disabled macroautophagy | disabled-macroautophagy | 2023 |
Antagonistic hallmarks (responses to damage)
Initially compensatory but become deleterious when chronic.
| Hallmark | Page | Introduced |
|---|---|---|
| Deregulated nutrient-sensing | deregulated-nutrient-sensing | 2013 |
| Mitochondrial dysfunction | mitochondrial-dysfunction | 2013 |
| Cellular senescence | cellular-senescence | 2013 |
Integrative hallmarks (the visible result)
The systemic-level manifestations.
| Hallmark | Page | Introduced |
|---|---|---|
| Stem cell exhaustion | stem-cell-exhaustion | 2013 |
| Altered intercellular communication | altered-intercellular-communication | 2013 |
| Chronic inflammation | chronic-inflammation | 2023 |
| Dysbiosis | dysbiosis | 2023 |
Crosswalk to SENS damage categories
| Hallmark | SENS category |
|---|---|
| Cellular senescence | sens-damage-categories > 3-death-resistant-cells-apoptosenes |
| Mitochondrial dysfunction | sens-damage-categories > 4-mitochondrial-mutations-mitosens |
| Stem cell exhaustion | sens-damage-categories > 1-cell-loss-and-atrophy-replenisens |
| Loss of proteostasis (intracellular) | sens-damage-categories > 5-intracellular-waste-products-lysosens |
| Loss of proteostasis (extracellular aggregates) | sens-damage-categories > 6-extracellular-waste-products-amylosens |
| Genomic instability (cancer angle) | sens-damage-categories > 2-division-obsessed-cells-oncosens |
| Altered intercellular communication (ECM stiffening) | sens-damage-categories > 7-extracellular-matrix-stiffening-glycosens |
The frames are not 1:1. SENS organizes by what kind of repair is needed; Hallmarks organizes by what kind of damage occurs. Several hallmarks (telomere attrition, epigenetic alterations, disabled macroautophagy, deregulated nutrient-sensing, chronic inflammation, dysbiosis) have no direct SENS counterpart.
Quantifying the hallmarks: transcriptomic module clocks
The hallmarks are descriptive categories; a complementary, quantitative decomposition of aging into co-regulated molecular subsystems comes from the transcriptomic module-clock framework (transcriptomic-clock-tage, from tyshkovskiy-2026-universal-transcriptomic-hallmarks). Network analysis (WGCNA) of >11,000 mammalian transcriptomes resolved aging/mortality into ~28 co-expression modules — inflammation, interferon signalling, mitochondrial/OXPHOS, chromatin modification, ECM/EMT, and others — each with its own clock that can be accelerated or rejuvenated independently. This is not a competing framework but a measurement layer over the hallmarks: immune/inflammation modules map onto chronic-inflammation and disabled-adaptive-immunity; mitochondrial/OXPHOS modules onto mitochondrial-dysfunction; chromatin modules onto epigenetic-alterations. Its practical contribution is letting interventions be ranked by which subsystem they target (chronic disease → inflammatory modules; caloric restriction & Klotho deficiency → metabolic modules), directly serving the “what interventions target [hallmark]?” query at module resolution.
Open questions about the framework
contradictory-evidence — Whether the hallmarks are causally independent or reducible to a smaller set of upstream drivers (e.g., DNA damage, mitochondrial dysfunction) is debated.
no-mechanism — Causal interconnections between hallmarks are mostly hypothesized; few have been experimentally dissected.