Hallmarks of aging: An expanding universe
TL;DR
Decade-later update to the 2013 paper. Adds three new hallmarks — disabled-macroautophagy, chronic-inflammation, and dysbiosis — bringing the total to twelve. The paper retains the 2013 Primary / Antagonistic / Integrative tripartite categorization and assigns the three new hallmarks to it; it also overlays a new “strata of organismal organization” mapping (Figure 7) that places each hallmark on a scale from molecules → meta-organism.
The 12 hallmarks
Per the abstract and Figure 1 (“The hallmarks of aging” wheel diagram, p. 244):
- Genomic instability
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Disabled macroautophagy (new)
- Deregulated nutrient-sensing
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
- Chronic inflammation (new)
- Dysbiosis (new)
Categorization (Figure 1)
The 2013 Primary / Antagonistic / Integrative scheme is retained and extended:
| Category | Hallmarks |
|---|---|
| Primary (causes of damage) | Genomic instability, Telomere attrition, Epigenetic alterations, Loss of proteostasis, Disabled macroautophagy |
| Antagonistic (responses to damage) | Deregulated nutrient-sensing, Mitochondrial dysfunction, Cellular senescence |
| Integrative (consequences when damage cannot be compensated) | Stem cell exhaustion, Altered intercellular communication, Chronic inflammation, Dysbiosis |
Verified directly against Figure 1 (p. 244) and the “Integration of hallmarks” section (p. 266), which restates the causal cascade: “the primary hallmarks… unambiguously contribute to the aging process. The antagonistic hallmarks… reflect responses to damage [and] play a more nuanced role… Finally, the integrative hallmarks arise when the accumulated damage inflicted by the primary and antagonistic hallmarks cannot be compensated any more, resulting in stem cell exhaustion, intercellular communication alterations including ECM damage, chronic inflammation, and dysbiosis.”
What changed from 2013
| Change | Detail |
|---|---|
| Added | disabled-macroautophagy — elevated from a sub-aspect of proteostasis. Justification (p. 244): “macroautophagy does not only affect proteins but can target entire organelles and non-proteinaceous macromolecules, justifying its discussion as a separate entity.” Categorized Primary. |
| Added | chronic-inflammation — “inflammaging” elevated from a subset of altered intercellular communication. Justification (p. 244): the 2013 altered-intercellular-communication hallmark was “too vast, requiring a separate discussion of chronic inflammation and age-associated dysbiosis.” Categorized Integrative. |
| Added | dysbiosis — gut microbiome composition shifts; carved out alongside chronic inflammation from the original altered-intercellular-communication hallmark. Categorized Integrative. |
| New overlay | Figure 7 maps each hallmark to a “stratum of organismal organization” (molecules → organelles → cells → supracellular units → organs → organ systems → systemic circuitries → meta-organism), creating an orthogonal axis to the Primary/Antagonistic/Integrative scheme. |
| New connection | Hallmarks of aging are explicitly connected to the eight “hallmarks of health” (LĂłpez-OtĂn & Kroemer 2021): spatial compartmentalization, maintenance of homeostasis, adequate responses to stress. |
| Causal cascade | The 2013 hierarchical Primary → Antagonistic → Integrative cascade is preserved and restated more explicitly (p. 266, “Integration of hallmarks”); the paper also adds a Figure 1 statement that hallmarks “are interconnected” and “experimental accentuation or attenuation of one specific hallmark usually affects other hallmarks as well.” |
The original 9 hallmarks’ definitions are not materially redefined; the discussions are updated with post-2013 evidence (e.g., heterochronic parabiosis single-cell transcriptomics, OSKM partial reprogramming, NAD+ precursors, senolytics in human Phase 1/2 trials, NLRP3 / canakinumab data from CANTOS).
Notable model-organism / human evidence updates (Table 1)
The paper’s Table 1 (pp. 246–250) compiles “examples of anti-aging effects of hallmark-targeted interventions in mammals,” including a number of human trials worth tracking on entity pages:
- Senolytics in humans: dasatinib + quercetin Phase 1 trials in pulmonary fibrosis (Justice et al.) and diabetic kidney disease (Hickson et al.).
- NAD+ precursors in humans: oral NMN in prediabetic women (Yoshino et al., Phase 3); oral NR in Parkinson’s (Brakedal et al., Phase 1).
- Urolithin A in humans: randomized Phase 2 in middle-aged adults — improved aerobic endurance, reduced plasma CRP (Singh et al.).
- Caloric restriction in humans: 14% × 2 years (CALERIE-style; Spadaro et al., Phase 2) — improved thymopoiesis, reduced PLA2G7.
- Anti-inflammatory in humans: canakinumab (anti-IL-1β) in CANTOS Phase 3 — reduced incidence of hypertension, diabetes, recurrent MI, lung cancer (Ridker et al.).
- Akkermansia muciniphila in humans: pasteurized oral admin in obese/diabetic patients — improved metabolic parameters (Depommier et al., randomized Phase 1/2).
- Elamipretide in humans: Phase 2/3 in Barth syndrome (Reid Thompson et al.) — improved muscle/cardiac parameters.
These are candidates for adding to entity pages on the respective compounds and processes; this study page lists them but full quantitative extraction belongs on those pages.
See also
- lopez-otin-2013-hallmarks-of-aging — the original (verified).
- hallmarks-of-aging — wiki MOC integrating both papers.