The Hallmarks of Aging
TL;DR
Foundational review proposing nine cellular and molecular hallmarks of aging, organized into three causally-related categories — Primary (causes of damage), Antagonistic (compensatory responses that turn deleterious), and Integrative (system-level outcomes). Established the criteria that subsequent candidate hallmarks must satisfy and the conceptual framework that organizes most modern aging research.
The nine hallmarks (Figure 1)
| Category | Hallmark |
|---|---|
| Primary (causes of damage) | genomic-instability |
| Primary | telomere-attrition |
| Primary | epigenetic-alterations |
| Primary | loss-of-proteostasis |
| Antagonistic (responses to damage) | deregulated-nutrient-sensing |
| Antagonistic | mitochondrial-dysfunction |
| Antagonistic | cellular-senescence |
| Integrative (culprits of phenotype) | stem-cell-exhaustion |
| Integrative | altered-intercellular-communication |
(4 Primary + 3 Antagonistic + 2 Integrative = 9.)
Hallmark criteria
A candidate hallmark must satisfy three criteria:
- Manifests during normal aging.
- Experimental aggravation accelerates aging.
- Experimental amelioration retards the aging process and increases healthy lifespan.
The paper notes that the third criterion is the most difficult to achieve and that “not all of the hallmarks are fully supported yet by interventions that succeed in ameliorating aging” — a caveat tempered by the observation that hallmarks are interconnected, so amelioration of one may improve others.
The three-category causal cascade (Figure 6)
The categorization is not just descriptive — it’s a proposed causal hypothesis:
The primary hallmarks could be the initiating triggers whose damaging consequences progressively accumulate with time. The antagonistic hallmarks, being in principle beneficial, become progressively negative in a process that is partly promoted or accelerated by the primary hallmarks. Finally, the integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by tissue homeostatic mechanisms.
The “common characteristic of the primary hallmarks is the fact that they are all unequivocally negative.” Antagonistic hallmarks “have opposite effects depending on their intensity” — beneficial at low levels, deleterious when chronic.
Proposed therapeutic strategies (Figure 7)
The paper enumerates intervention strategies aligned to each hallmark with at-the-time existing proof-of-principle in mice:
| Hallmark | Intervention strategy |
|---|---|
| Genomic instability | Elimination of damaged cells |
| Telomere attrition | Telomerase reactivation |
| Epigenetic alterations | Epigenetic drugs |
| Loss of proteostasis | Activation of chaperones and proteolytic systems |
| Deregulated nutrient sensing | Dietary restriction; IIS and mTOR inhibition; AMPK and sirtuin activation |
| Mitochondrial dysfunction | Mitohormetics, mitophagy |
| Cellular senescence | Clearance of senescent cells |
| Stem cell exhaustion | Stem-cell-based therapies |
| Altered intercellular communication | Anti-inflammatory drugs; blood-borne rejuvenation factors |
Significance
- One of the most-cited papers in modern aging research.
- Defined the vocabulary and categorization used by virtually all subsequent hallmark-organized work.
- Updated and expanded by the same authors in 2023 → lopez-otin-2023-hallmarks-expanding-universe adds three new hallmarks (disabled macroautophagy, chronic inflammation, dysbiosis), bringing the total to twelve.
See also
- hallmarks-of-aging — the wiki MOC built on this framework.
- sens-damage-categories — alternative organizing framework with partial overlap.