The hallmarks of aging are 12 biological processes that drive age-related decline. From genomic instability to dysbiosis, we review the evidence and the interventions available today.
The hallmarks of aging are the 12 biological mechanisms that, together, explain why we age. They were first defined in 2013 by Carlos López-Otín and colleagues in a landmark paper published in Cell that reshaped longevity research, and updated in 2023 with three additional hallmarks (López-Otín et al., Cell 2023, PMID: 36599349). The framework doesn't just describe what goes wrong with age: it identifies what can be measured and, most importantly, what can be done about it.
This article explains each hallmark in accessible language, presents the scientific evidence behind it, and connects each mechanism to the interventions available today — from lifestyle habits to clinical treatments offered at longevity clinics like Progevita.
From the 2013 paper to the 2023 expanding universe
The original López-Otín paper published in Cell in 2013 (PMID: 23746838) identified 9 hallmarks organized into three categories: primary causes of damage, compensatory responses, and the result of those responses failing. The paper accumulated over 10,000 citations and became the reference framework for all aging research.
In January 2023, the team published an update titled "Hallmarks of aging: An expanding universe" that incorporated three new hallmarks: disabled macroautophagy (previously included within loss of proteostasis), chronic inflammation (inflammaging, previously part of altered intercellular communication), and dysbiosis (microbiome imbalance). The result: 12 interconnected hallmarks that provide a complete map of biological decline.
The 12 hallmarks of aging
1. Genomic instability
Your DNA accumulates damage throughout life: mutations, breaks, copying errors. DNA repair mechanisms lose efficiency with age, and the result is a buildup of mutations that can lead to cancer, cellular dysfunction, and accelerated aging. Each human cell is estimated to accumulate roughly 40 mutations per year (Martincorena et al., Science, 2015, PMID: 26449472).
What you can do: Avoid known mutagens (tobacco, excessive UV radiation, alcohol), maintain adequate NAD+ levels (an essential cofactor for repair enzymes like PARP), and prioritize deep sleep — the phase when DNA repair mechanisms are most active. NAD+ therapy directly supports these repair pathways.
2. Telomere attrition
Telomeres are the protective caps at the ends of chromosomes. With each cell division they shorten slightly, and when they become too short the cell enters senescence or dies. The enzyme telomerase can rebuild them, but its activity declines in most adult tissues. Elizabeth Blackburn received the Nobel Prize in 2009 for this discovery.
What you can do: Moderate aerobic exercise is associated with longer telomeres (Werner et al., European Heart Journal, 2019, PMID: 30496500). Chronic stress shortens them (Epel et al., PNAS, 2004). The Mediterranean diet also shows a positive association with telomere length. No approved drugs safely lengthen telomeres in humans.
3. Epigenetic alterations
The epigenome is the system of "switches" that determines which genes are expressed and which remain silenced. With age, these patterns become deregulated: genes that should be off turn on and vice versa. Epigenetic clocks like GrimAge (Lu et al., Aging, 2019, PMID: 30669119) measure these changes to calculate biological age, which can differ by up to 20 years from chronological age.
What you can do: Regular exercise, a diet rich in methyl donors (folate, B12, choline), caloric restriction, and intermittent fasting have been shown to positively influence epigenetic markers. Measuring your epigenetic age lets you evaluate whether your interventions are working.
4. Loss of proteostasis
Proteins must fold correctly to function. With age, quality control systems — such as proteasomes and chaperones — lose efficiency. Misfolded proteins accumulate and form toxic aggregates. This process underlies Alzheimer's disease (beta-amyloid plaques) and Parkinson's (alpha-synuclein).
What you can do: Autophagy is the primary mechanism for clearing damaged proteins (see hallmark 5). Resistance training stimulates muscle protein turnover. Saunas and heat exposure activate heat shock proteins (HSPs), which function as molecular chaperones.
5. Disabled macroautophagy
Autophagy is the cell's recycling system: the cell degrades and reuses its own damaged components. Yoshinori Ohsumi received the Nobel Prize in 2016 for describing this mechanism. With age, autophagy becomes less efficient, and cellular waste accumulates. In the 2023 update, López-Otín elevated it to an independent hallmark due to the accumulated evidence of its central role in aging (Fernández et al., Nature, 2018, PMID: 30323288).
What you can do: Intermittent fasting is the most studied autophagy activator. Exercise also induces it (He et al., Nature, 2012). Compounds like spermidine (found in wheat germ, soybeans, aged cheeses) and resveratrol show pro-autophagic effects in preclinical studies. Supervised therapeutic fasting intensifies this process.
6. Deregulated nutrient-sensing
Cells have sophisticated sensors that detect nutrient availability and adjust metabolism. The four main pathways are: mTOR (cell growth), AMPK (energy sensor), sirtuins (NAD+-dependent metabolic regulators), and insulin/IGF-1 (growth signaling). With age, these pathways become deregulated: mTOR becomes overactive, AMPK loses sensitivity, and sirtuins decrease their activity due to declining NAD+ levels.
What you can do: Caloric restriction and intermittent fasting reduce mTOR activity and activate AMPK. Rapamycin, an mTOR inhibitor, extends lifespan in mice and is being investigated in humans (Dog Aging Project TRIAD trial, 2025). Maintaining optimal NAD+ levels supports sirtuin function. Reducing processed animal protein intake lowers IGF-1 signaling.
7. Mitochondrial dysfunction
Mitochondria are the cell's power plants. They produce the ATP that fuels all biological processes. With age, they accumulate damage to their own DNA, lose efficiency in the electron transport chain, and generate more free radicals. The result: less energy, more oxidative stress, more inflammation. NAD+ levels drop by approximately 50% between ages 40 and 60 (Massudi et al., PLoS One, 2012, PMID: 22870241), directly compromising mitochondrial function. Read more in our article on mitochondrial dysfunction and aging.
What you can do: Aerobic exercise (especially high-intensity intervals) stimulates mitochondrial biogenesis. NAD+ therapy restores levels of this essential cofactor. Cold exposure activates thermogenesis and mitochondrial function in brown adipose tissue. CoQ10 and PQQ are cofactors that support the respiratory chain.
8. Cellular senescence
Senescent cells are cells that have stopped dividing but don't die: they remain active, secreting a cocktail of inflammatory molecules called the SASP (senescence-associated secretory phenotype). In small numbers they're useful — they aid wound healing — but with age they accumulate and generate chronic inflammation, damaging surrounding tissue. Kirkland and Tchkonia demonstrated in 2017 that eliminating them with senolytic drugs rejuvenates tissues in mice (PMID: 28416161). In 2024, a pilot trial of dasatinib + quercetin showed cognitive improvement in older adults with mild cognitive impairment (Cedars-Sinai, 2024). Read more about cellular senescence and senolytics.
What you can do: Exercise reduces the senescent cell burden. Quercetin (onions, apples, broccoli) and fisetin (strawberries) have senolytic properties in preclinical studies. Therapeutic plasmapheresis removes circulating SASP factors from the plasma. Ozone therapy modulates the associated inflammatory response.
9. Stem cell exhaustion
Stem cells are the body's repair reserve. They regenerate tissues, repair damage, and maintain homeostasis. With age, their numbers decline and the remaining ones lose their ability to differentiate. The result: tissues regenerate poorly, wounds heal more slowly, the immune system weakens. Conboy's seminal study (2005, PMID: 15703760) demonstrated that exposing aged stem cells to a young environment partially restores their function — one of the scientific foundations for plasmapheresis in longevity medicine.
What you can do: Regular exercise maintains stem cell niches. Quality sleep is essential for tissue regeneration. Therapeutic plasmapheresis seeks to replicate Conboy's findings by removing inhibitory factors from the plasma. Avoiding chronic inflammation protects the niches where stem cells reside.
10. Altered intercellular communication
Cells don't work in isolation: they constantly communicate through hormonal, immune, and neuroendocrine signals. With age, this communication deteriorates. Inflammatory signals increase, protective hormones decline, and the immune system loses its ability to distinguish real threats from self-tissue (immunosenescence). The result is a systemic environment that accelerates aging of all cells, even healthy ones.
What you can do: Maintain hormonal balance (testosterone, estradiol, thyroid hormone, cortisol) through clinical monitoring and, when indicated, hormone replacement therapy. Anti-inflammatory nutrition reduces systemic damage signals. Plasmapheresis cleanses the plasma of circulating factors that perpetuate decline.
11. Chronic inflammation (inflammaging)
Elevated to an independent hallmark in 2023, inflammaging is a state of low-grade systemic inflammation without apparent infection, associated with virtually all chronic diseases of aging: cardiovascular, neurodegenerative, metabolic, and oncological. The term was coined by Claudio Franceschi in 2000 (Franceschi et al., Nat Rev Endocrinol, 2018, PMID: 29740120). It can be measured through biomarkers like hsCRP, suPAR, IL-6, and TNF-alpha.
What you can do: The Mediterranean diet reduces inflammatory markers (PREDIMED study, Estruch et al., NEJM, 2018, PMID: 29897866). Regular exercise lowers CRP by 20-30%. Intermittent fasting modulates inflammatory cytokines. Ozone therapy activates the Nrf2 pathway, one of the body's main antioxidant systems. Longevity biomarkers allow you to monitor your inflammation levels.
12. Dysbiosis
The last hallmark added in 2023 recognizes that the gut microbiota — the trillions of microorganisms inhabiting your intestines — plays a direct role in aging. With age, microbial diversity decreases, pro-inflammatory bacteria increase, and the intestinal barrier becomes more permeable ("leaky gut"). This imbalance contributes to systemic inflammation, affects immunity, and has been linked to neurodegenerative diseases through the gut-brain axis.
What you can do: Consume 30+ types of plants per week (the recommendation from the American Gut project, McDonald et al., mSystems, 2018). Prioritize fermented foods (yogurt, kefir, kimchi, sauerkraut) that increase microbial diversity. Minimize ultra-processed foods and artificial sweeteners. Prebiotic fiber (inulin, resistant starch, pectins) feeds beneficial bacteria. Avoid unnecessary antibiotic use.
The three levels of the hallmarks
López-Otín organized the 12 hallmarks into three hierarchical levels that explain how they interact:
| Level | Hallmarks | Role |
|---|---|---|
| Primary causes | Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy | Molecular damage that accumulates over time |
| Antagonistic responses | Deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence | Responses that initially compensate for damage but become harmful |
| Integrative hallmarks | Stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis | Functional consequences of accumulated failure |
What matters about this hierarchy is that the hallmarks are not independent: mitochondrial dysfunction generates oxidative stress that causes genomic instability. Senescent cells secrete inflammatory factors (SASP) that produce inflammaging. Dysbiosis feeds systemic inflammation that, in turn, exhausts stem cells. Intervening on one hallmark has cascading effects on the others.
Which hallmarks does each Progevita treatment address?
At Progevita, we apply evidence-based treatments that act on multiple hallmarks simultaneously. This table shows the main connections:
| Treatment | Hallmarks addressed | Primary mechanism |
|---|---|---|
| NAD+ IV therapy | Mitochondrial dysfunction, nutrient-sensing, genomic instability | Restores essential cofactor for sirtuins, PARP, and respiratory chain |
| Ozone therapy | Inflammaging, mitochondrial dysfunction, cellular senescence | Activates Nrf2, modulates inflammatory response, improves tissue oxygenation |
| Therapeutic plasmapheresis | Intercellular communication, senescence (SASP), stem cell exhaustion | Removes pro-inflammatory and pro-aging factors from plasma |
| Orthomolecular IV therapy | Loss of proteostasis, mitochondrial dysfunction | Provides cofactors (vitamin C, glutathione, minerals) for cellular function |
| Nutritional program | Dysbiosis, inflammaging, nutrient-sensing | Mediterranean diet, prebiotic fiber, natural anti-inflammatories |
| Prescribed exercise | All (pleiotropic effect) | Mitochondrial biogenesis, autophagy, senescent cell clearance, telomeres |
| Biomarker assessment | All (diagnostic) | VO2max, epigenetic age, hsCRP, suPAR, body composition |
The 5 interventions with the strongest cross-cutting evidence
Some interventions act on so many hallmarks that they deserve special mention. Ranked by level of evidence in humans:
1. Regular exercise (aerobic + resistance). This is the intervention with the most evidence for slowing aging. It improves mitochondrial function, induces autophagy, reduces the senescent cell burden, lowers inflammation, protects telomeres, and keeps stem cells active. A meta-analysis by Mandsager et al. (JAMA Network Open, 2018, PMID: 30382293) showed that each additional MET of cardiorespiratory fitness is associated with 13% lower all-cause mortality.
2. Mediterranean-style nutrition. The PREDIMED study demonstrated a 30% reduction in cardiovascular events (Estruch et al., NEJM, 2018, PMID: 29897866). Anti-inflammatory nutrition reduces inflammaging, improves microbial diversity, and provides compounds with natural senolytic activity (quercetin, fisetin, resveratrol).
3. Intermittent fasting / caloric restriction. Inhibits mTOR, activates AMPK and autophagy, improves insulin sensitivity, and reduces inflammatory markers. De Cabo and Mattson published the definitive review in NEJM in 2019 (PMID: 31881139). Read our guide to intermittent fasting and autophagy.
4. Quality sleep (7-9 hours). During deep sleep, DNA repair mechanisms activate, the glymphatic system cleans the brain (clearing beta-amyloid), memory consolidates, and hormones regulate. Chronic sleep deprivation accelerates epigenetic age and increases inflammatory markers.
5. Chronic stress management. Sustained stress shortens telomeres (Epel et al., PNAS, 2004), elevates cortisol, activates inflammation, and alters the microbiota. Practices like meditation, nature exposure, and meaningful social relationships (Holt-Lunstad et al., Perspectives on Psychological Science, 2015, PMID: 25910392) partially reverse these effects.
Can aging be reversed?
The most common question. The honest answer: partially, and it depends on the hallmark. Some are more reversible than others:
| Hallmark | Reversible? | State of the science |
|---|---|---|
| Inflammaging | Yes, significantly | Diet, exercise, and ozone therapy reduce markers within weeks |
| Mitochondrial dysfunction | Partially | NAD+ and exercise restore function, but don't eliminate mitochondrial DNA mutations |
| Cellular senescence | Yes (elimination) | Senolytics in Phase I-II clinical trials (dasatinib + quercetin) |
| Dysbiosis | Yes | Dietary changes modify microbiota within 2-4 weeks |
| Epigenetic alterations | Partially | Interventions reduce epigenetic age measured by clocks |
| Disabled macroautophagy | Yes (reactivation) | Fasting and exercise effectively reactivate it |
| Deregulated nutrient-sensing | Yes | Caloric restriction and fasting restore sensitivity |
| Loss of proteostasis | Partially | Less direct evidence; autophagy and chaperones help |
| Telomere attrition | Limited | Exercise slows shortening; active elongation is experimental |
| Genomic instability | No (prevention) | Further damage can be prevented but existing mutations can't be reversed |
| Stem cell exhaustion | Partially | Plasmapheresis and rejuvenation factors under investigation |
| Altered intercellular communication | Partially | Hormonal balance and SASP reduction improve signaling |
The most effective approach isn't attacking a single hallmark but addressing several at once with interventions that have pleiotropic effects: exercise, nutrition, fasting, sleep, and targeted clinical treatments like those offered in Progevita's programs.
Frequently asked questions
What are the hallmarks of aging?
The hallmarks of aging are 12 biological processes identified by López-Otín et al. (Cell, 2023) that explain why the human body deteriorates with age. They range from DNA damage accumulation to chronic inflammation and gut dysbiosis. This scientific framework is the main reference in longevity research.
What are the 12 hallmarks of aging?
The 12 hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation (inflammaging), and dysbiosis.
Can you slow aging by targeting the hallmarks?
Yes, partially. Interventions like regular exercise, the Mediterranean diet, intermittent fasting, and quality sleep act on multiple hallmarks simultaneously. Clinical treatments like NAD+ therapy, ozone therapy, and plasmapheresis address specific hallmarks with growing evidence. Aging can't be stopped entirely, but its progression can be significantly slowed.
How many hallmarks were there originally and how many are there now?
The original 2013 paper defined 9 hallmarks. The 2023 update added 3 new ones: disabled macroautophagy (previously part of proteostasis), chronic inflammation (previously included in intercellular communication), and dysbiosis (gut microbiome). The current total is 12 hallmarks.
Which hallmark is easiest to address?
Inflammaging (chronic inflammation) and dysbiosis are the most modifiable hallmarks through lifestyle changes. The Mediterranean diet, exercise, and fermented foods can reduce inflammation and improve microbial diversity within weeks. Results can be monitored with biomarkers like high-sensitivity CRP and suPAR.
How do the hallmarks of aging relate to longevity clinics?
Modern longevity clinics design their programs around the hallmarks of aging. At Progevita, each patient receives a biomarker assessment reflecting the state of multiple hallmarks, and a personalized plan of treatments and habits to address the most compromised ones. The goal is to reduce biological age and extend healthy life years (healthspan).
References
- López-Otín C, et al. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278 (PMID: 36599349).
- López-Otín C, et al. The Hallmarks of Aging. Cell. 2013;153(6):1194-1217 (PMID: 23746838).
- Martincorena I, et al. Somatic mutant clones colonize the human esophagus with age. Science. 2015;348(6238):880-886 (PMID: 26449472).
- Werner CM, et al. Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length. European Heart Journal. 2019;40(1):34-46 (PMID: 30496500).
- Lu AT, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging. 2019;11(2):303-327 (PMID: 30669119).
- Fernández ÁF, et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature. 2018;558:136-140 (PMID: 30323288).
- Massudi H, et al. Age-Associated Changes in Oxidative Stress and NAD+ Metabolism in Human Tissue. PLoS One. 2012;7(7):e42357 (PMID: 22870241).
- Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017;21:21-28 (PMID: 28416161).
- Franceschi C, et al. Inflammaging and anti-inflammaging: a systemic perspective. Nat Rev Endocrinol. 2018;14(10):576-590 (PMID: 29740120).
- Estruch R, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. NEJM. 2018;378(25):e34 (PMID: 29897866).
- De Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. NEJM. 2019;381(26):2541-2551 (PMID: 31881139).
- Mandsager K, et al. Association of Cardiorespiratory Fitness With Long-term Mortality. JAMA Network Open. 2018;1(6):e183605 (PMID: 30382293).
- Holt-Lunstad J, et al. Loneliness and Social Isolation as Risk Factors for Mortality. Perspectives on Psychological Science. 2015;10(2):227-237 (PMID: 25910392).
- McDonald D, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18 (PMID: 29795809).
- Conboy IM, et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433:760-764 (PMID: 15703760).
This article is for informational purposes and does not replace individual medical advice. To design a longevity plan tailored to your profile, consult a qualified healthcare professional.
Want to know which hallmarks of aging are most active in your case? Request a personalized assessment at Progevita — Balneario de Cofrentes, Valencia, Spain.