# Hallmarks of aging

Rating: Early — Mostly animal or cell studies; few or uncontrolled human data
Type: Mechanism
Updated: 2026-08-01
Canonical: https://heretic.bio/articles/hallmarks-of-aging.html

> The Hallmarks of Aging is a consensus framework listing 12 interconnected processes, such as genomic instability, cellular senescence and inflammaging, that jointly drive aging. It was proposed in 2013 with nine hallmarks and expanded to twelve in 2023. It is a research scaffold built by expert agreement, not an empirical classification, and the evidence behind each hallmark differs.

> The Hallmarks of Aging are a consensus conceptual framework (not an empirical classification) identifying 12 interconnected biological processes that collectively drive aging. First proposed in 2013 with 9 hallmarks, expanded to 12 in the 2023 update. The framework has become the dominant scaffold for geroscience research and clinical trial design.

## 1\. Origin and Evolution

### 2013 (original — 9 hallmarks)

López-Otín, Blasco, Partridge, Serrano & Kroemer, _Cell_ 153(6):1194-1217 (PMID [23746838](https://pubmed.ncbi.nlm.nih.gov/23746838/)). Built on the prior success of "Hallmarks of Cancer" (Hanahan & Weinberg, 2000/2011). The 9 hallmarks were organised into three tiers: \- **Primary (4):** Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis \- **Antagonistic (3):** Deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence \- **Integrative (2):** Stem cell exhaustion, altered intercellular communication

### 2023 update (12 hallmarks)

López-Otín, Blasco, Partridge, Serrano & Kroemer, _Cell_ 186(2):243-378 (PMID [36599349](https://pubmed.ncbi.nlm.nih.gov/36599349/)). Three new hallmarks added: **disabled macroautophagy, chronic inflammation (inflammaging), and dysbiosis**. Plus a new tier — **mechanistic hallmarks** — distinguishing causal mechanisms (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy) from those that emerge as integrative outcomes.

### 2024 conceptual commentary

Tartiere, Freije & López-Otín, _Front Aging_ 5:1334261 (DOI [10.3389/fragi.2024.1334261](https://doi.org/10.3389/fragi.2024.1334261)). Self-assessment of the framework's impact 10+ years on. Key conclusions: \- The Hallmarks have served as a framework not only for aging research but also for adjacent fields (cancer, neurodegeneration, metabolic disease) \- Hallmarks should be viewed as **interdependent and hierarchically organized** , not as independent processes \- New candidates (cell size, RNA processing dysregulation, impaired lipid metabolism, ECM dynamics, extracellular vesicles, mechanical properties, splicing dysregulation) were evaluated — **none formally adopted** because they fail at least one of the three criteria \- The list is intentionally **not closed** — it is a living framework

## 2\. The Three Criteria for a Hallmark

Per the 2023 _Cell_ update (Tartiere 2024 reiterates): a candidate hallmark must satisfy **all three** : 1\. **Appear during physiological (normal) aging** 2\. **Accelerate aging when experimentally aggravated** (gain-of-function) 3\. **Slow, delay, or reverse aging when experimentally alleviated** (loss-of-function / therapeutic intervention)

This criterion-based approach is why several plausible candidates (cell size, ECM dynamics, RNA processing dysregulation, impaired lipid metabolism) remain excluded as of 2026 — the in vivo acceleration/amelioration evidence is incomplete.

## 3\. The 12 Hallmarks — Detailed

### PRIMARY / MECHANISTIC HALLMARKS (damage initiators)

#### 1\. Genomic instability

Accumulation of DNA damage over time: single- and double-strand breaks, point mutations, deletions, insertions, chromosomal rearrangements, transposon activation, mitochondrial DNA mutations. **In mammals, the species-specific rate of somatic mutation decreases as lifespan increases** (Cagan et al., 2022, _Nature_) — long-lived species have more accurate DNA repair. Interventions: NAD+ precursors (support PARP-mediated single-strand repair), sirtuin activation, DNA repair pathway support.

#### 2\. Telomere attrition

Progressive shortening of chromosome ends with each cell division in cells with linear chromosomes (most somatic cells). Telomerase knockout mice show premature aging (Jaskelioff et al., 2011, _Nature_). **Telomere dysfunction can occur independent of length** (Hewitt et al., 2012; Victorelli et al., 2019) — DNA damage at telomeres, not just shortening per se, drives aging. Interventions: [TA-65 (cycloastragenol)](telomere-science.html), [epitalon](epitalon-aedg-tetrapeptide-telomerase-pineal-axis-and-geroprotective-evidence.html), gene therapy (Libella, BioViva — controversial). See [Telomere Science](telomere-science.html).

#### 3\. Epigenetic alterations

Age-associated changes in DNA methylation, histone modifications, chromatin remodeling — these are largely environment- and lifestyle-driven and partially reversible. Histone acetylation changes causally contribute to aging (Wang et al., 2021). Connected to other hallmarks: mitochondrial dysfunction → altered acetyl-CoA export → chromatin changes → stem cell pluripotency loss (Pouikli et al., 2021). Interventions: [partial Yamanaka reprogramming](partial-epigenetic-reprogramming.html), [bioregulator peptides](epitalon-aedg-tetrapeptide-telomerase-pineal-axis-and-geroprotective-evidence.html), sirtuin activators (resveratrol, NAD+).

#### 4\. Loss of proteostasis

Decline in protein synthesis fidelity, folding (chaperones), and degradation (autophagy, ubiquitin-proteasome). Induces protein aggregation (β-amyloid, α-synuclein, lipofuscin). Induction of translation errors accelerates aging in mice (Shcherbakov et al., 2022). Interventions: [fasting/spermidine-induced autophagy](autophagy.html), [rapamycin](rapamycin-mtor-inhibition-pearl-trial-evidence-and-clinical-translation.html), [NAD+](nad-and-sirtuin-activators.html).

#### 5\. Disabled macroautophagy (NEW 2023)

Age-related decline in autophagic flux — the bulk degradation of damaged organelles, misfolded proteins, and pathogens via lysosomes. Closely linked to loss of proteostasis but split into its own hallmark because autophagy defects specifically drive accumulation of damaged mitochondria (mitophagy) and aggregate-prone proteins. Interventions: [spermidine](spermidine-autophagy-and-longevity.html), [rapamycin](rapamycin-mtor-inhibition-pearl-trial-evidence-and-clinical-translation.html), fasting, exercise, [NAD+](nad-and-sirtuin-activators.html).

### ANTAGONISTIC HALLMARKS (initially protective, become detrimental with chronic activation)

#### 6\. Deregulated nutrient sensing

Failure of nutrient-sensing pathways (insulin/IGF-1, mTOR, AMPK, sirtuins, FGF21). These pathways evolved to protect during scarcity but become dysregulated in calorie-replete modern environments. mTORC1 inhibition extends lifespan in yeast, worms, flies, and mice (Partridge et al., 2020). Interventions: [rapamycin](rapamycin-mtor-inhibition-pearl-trial-evidence-and-clinical-translation.html), [metformin](metformin-and-rapamycin.html), caloric restriction, FMD. See [mTOR and AMPK Pathways](mtor-and-ampk-pathways.html).

#### 7\. Mitochondrial dysfunction

Declining mitochondrial renewal and function with age → accumulation of damaged mitochondria producing excess ROS. Causes permeabilization, inflammation, and cell death (Amorim et al., 2022). **Mitohormesis paradox:** low-grade mitochondrial stress in youth triggers adaptive responses that promote longevity — chronic dysfunction does the opposite. Interventions: [NAD+](nad-and-sirtuin-activators.html), CoQ10, urolithin A, exercise, [Mitochondrial Health](mitochondrial-health.html).

#### 8\. Cellular senescence

Cell-cycle arrest in response to damage — protective in youth (anti-cancer, wound healing) but accumulates with age, driving SASP (senescence-associated secretory phenotype) that promotes chronic inflammation. Senolytic interventions improve physical function and extend lifespan in mice (Xu et al., 2018, _Nat Med_). Interventions: [dasatinib + quercetin, fisetin, navitoclax](senolytics.html). See [Senolytic Therapeutics - Evidence and Competitive Landscape](senolytics.html).

### INTEGRATIVE HALLMARKS (tissue-level consequences)

#### 9\. Stem cell exhaustion

Decline in tissue regenerative capacity due to accumulated damage in stem cell populations. Partial reprogramming (OSK or OSKM Yamanaka factors, pulsed) extends lifespan in progeroid mice (Ocampo et al., 2016, _Cell_) and is now in human trials. Interventions: [partial reprogramming](partial-epigenetic-reprogramming.html), exercise, GDF11, [NAD+](nad-and-sirtuin-activators.html).

#### 10\. Altered intercellular communication

Includes: inflammatory cytokines, SASP, blood-borne factors with pro-aging effects, neuroendocrine changes, declined immune surveillance. **Heterochronic parabiosis evidence:** blood from old mice induces aging signatures in young mice; young blood partially reverses old phenotypes (Rebo et al., 2016; Ximerakis et al., 2023). Interventions: anti-inflammatory protocols, [therapeutic plasma exchange](therapeutic-plasma-exchange-tpe.html).

#### 11\. Chronic inflammation ("inflammaging") (NEW 2023)

Persistent low-grade sterile inflammation driven by SASP, gut dysbiosis, NLRP3 inflammasome activation, damaged-self recognition. Cross-links with cellular senescence, dysbiosis, and altered intercellular communication. Closely tied to all major age-related diseases (atherosclerosis, Alzheimer's, T2D). Interventions: anti-inflammatory diet, NLRP3 inhibitors (in development), [GlyNAC](glycine-glynac-and-glutathione-precursors-evidence-taxonomy.html), [spermidine](spermidine-autophagy-and-longevity.html).

#### 12\. Dysbiosis (NEW 2023)

Age-associated shifts in gut microbiome composition — reduced diversity, expansion of pro-inflammatory taxa, loss of short-chain-fatty-acid producers. Drives inflammaging and metabolic dysfunction. Connected bidirectionally to inflammaging. Interventions: probiotics, prebiotics, FMT, dietary fiber, [GlyNAC](glycine-glynac-and-glutathione-precursors-evidence-taxonomy.html).

## 4\. Hierarchical Organization (López-Otín 2023, Tartiere 2024)

The hallmarks are **not independent** — they form a hierarchical network: \- **Primary/mechanistic** hallmarks (1–5) initiate damage accumulation \- **Antagonistic** hallmarks (6–8) are compensatory responses that become pathogenic when chronic \- **Integrative** hallmarks (9–12) emerge when homeostatic mechanisms are overwhelmed

Tartiere 2024 emphasizes that the 2023 update shifted toward viewing hallmarks as **interdependent** rather than independent — e.g., cellular senescence drives inflammaging, which accelerates epigenetic drift, which further exhausts stem cells.

## 5\. Cross-Species Validation

Tartiere 2024 reviews evidence that the same hallmarks modulate lifespan in both short-lived (mice, zebrafish) and long-lived (naked mole-rat, bowhead whale) species — and in non-aging cnidarian _Turritopsis dohrnii_. Hallmark modulation, not absence, is what differentiates long-lived from short-lived species. Hyper-long telomeres in mice (Muñoz-Lorente et al., 2019) improve multiple hallmarks simultaneously (genomic instability, senescence, mitochondrial dysfunction), supporting cross-hallmark interdependence.

## 6\. New Candidates Evaluated (Tartiere 2024)

Candidate | Status | Reason not adopted  
---|---|---  
**Cell size increase** | Considered, rejected | Rapamycin effect on cell size is confounded with mTOR inhibition; not all cell types (e.g., neurons) follow the inverse size-lifespan correlation  
**RNA processing dysregulation** | Considered, promising | Lacks in vivo acceleration/amelioration evidence; partially covered under epigenetic alterations  
**Impaired lipid metabolism** | Considered | Strong link to senescence and inflammation but causal evidence incomplete  
**Extracellular matrix (ECM) dynamics** | Considered, rejected | Recent review (Statzer et al., 2023) concluded ECM does not yet meet all three criteria; partially covered under altered intercellular communication  
**Extracellular vesicles (EVs)** | Considered, rejected | Subsumed under altered intercellular communication — adding would duplicate  
**Altered mechanical properties** | Considered | Copenhagen 2022 proposal; not formally adopted  
**Splicing dysregulation** | Considered | Limited in vivo intervention evidence  
  
## 7\. Criticisms and Limitations

  1. **Not empirically derived** — the hallmarks are expert consensus, not data-driven clustering. Different selection of authors could yield a different list.
  2. **Mammalian bias** — most evidence is from mice/humans; the framework may not generalize to all metazoans.
  3. **Cross-sectional** — captures population averages of aging, not individual trajectories. Biological age clocks ([PhenoAge, GrimAge, DunedinPACE](biological-age-clocks-measurement-and-interpretation.html)) attempt to address this.
  4. **Hierarchy is heuristic** — the primary/antagonistic/integrative division is useful but not strictly causal.
  5. **Hallmarks as drug targets** — many interventions hit multiple hallmarks (rapamycin, exercise, fasting) which makes the framework both more useful (network-targeting) and harder to interpret mechanistically.



## 8\. Connection to Health3 library Topics

Hallmark | library Page  
---|---  
Genomic instability | [NAD+ and Sirtuin Activators](nad-and-sirtuin-activators.html), [NAD+ Precursors and Telomere Biology - Evidence Audit](nad-and-sirtuin-activators.html)  
Telomere attrition | [Telomere Science](telomere-science.html)  
Epigenetic alterations | [Epitalon](epitalon-aedg-tetrapeptide-telomerase-pineal-axis-and-geroprotective-evidence.html), Khavinson Peptides (Russian Bioregulators), [Partial Epigenetic Reprogramming - Competitive Intelligence](partial-epigenetic-reprogramming.html)  
Loss of proteostasis | [Autophagy](autophagy.html)  
Disabled macroautophagy | [Spermidine - Autophagy and Longevity](spermidine-autophagy-and-longevity.html), [Autophagy](autophagy.html)  
Deregulated nutrient sensing | [mTOR and AMPK Pathways](mtor-and-ampk-pathways.html), [Rapamycin mTOR Inhibition - PEARL Trial Evidence](rapamycin-mtor-inhibition-pearl-trial-evidence-and-clinical-translation.html), [Metformin and Rapamycin](metformin-and-rapamycin.html)  
Mitochondrial dysfunction | [Mitochondrial Health](mitochondrial-health.html) (planned), [NAD+ and Sirtuin Activators](nad-and-sirtuin-activators.html)  
Cellular senescence | [Senolytics](senolytics.html), [Senolytic Therapeutics - Evidence and Competitive Landscape](senolytics.html)  
Stem cell exhaustion | [Muse Cell Therapy - Evidence Taxonomy](muse-cell-therapy-evidence-taxonomy-and-clinical-translation.html), [Partial Epigenetic Reprogramming - Competitive Intelligence](partial-epigenetic-reprogramming.html)  
Altered intercellular communication | [Therapeutic Plasma Exchange (TPE)](therapeutic-plasma-exchange-tpe.html), [Thymosin Alpha-1 - Immune Modulation Evidence](thymosin-alpha-1-immune-modulation-and-longevity-translation.html)  
Inflammaging | [GlyNAC and Glutathione Precursors - Evidence Taxonomy](glycine-glynac-and-glutathione-precursors-evidence-taxonomy.html)  
Dysbiosis | Gut Microbiome Optimization (planned)  
  
## 9\. Open Questions (2026)

  * Are 12 hallmarks enough, or does the list need to grow to ~15–20 to capture the full network? (Tartiere 2024: "not closed")
  * Which hallmarks are **causally upstream** of others, and which are downstream? (Network vs. hierarchy debate)
  * Can we define a quantitative **dosing protocol per hallmark** to slow aging? (Geroscience hypothesis — single intervention targeting multiple hallmarks is most likely to succeed)
  * Are hallmarks conserved across all aging taxa, or are some metazoan-specific? (Recent work on _T. dohrnii_ suggests conservation)

## Sources

1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217. PMID 23746838 . DOI 10.1016/j.cell.2013.05.039 (PubMed 23746838, DOI 10.1016/j.cell.2013.05.039)
2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-378. PMID 36599349 . DOI 10.1016/j.cell.2022.11.001 (PubMed 36599349, DOI 10.1016/j.cell.2022.11.001)
3. Tartiere AG, Freije JMP, López-Otín C. The hallmarks of aging as a conceptual framework for health and longevity research. Front Aging. 2024;5:1334261. DOI 10.3389/fragi.2024.1334261 . Local copy: Sources/Papers/doi_10.3389_fragi.2024.1334261.pdf (DOI 10.3389/fragi.2024.1334261)
4. Schmauck-Medina T, Molière A, Lautrup S, et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany NY). 2022;14(16):6829-6839. PMID 36040386 . DOI 10.18632/aging.204248 (PubMed 36040386, DOI 10.18632/aging.204248)
5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. PMID 21376230 (PubMed 21376230)