The 12 Hallmarks of Aging Explained in Plain English (2026 Update)

Scientists defined 12 specific ways your body breaks down with age. Understanding them changes how you think about supplements, diet, and everything else.

In 2013, a group of researchers published a paper called "The Hallmarks of Aging" that created the framework for understanding why we get old. They identified nine distinct biological processes that drive aging. In 2023, the framework was updated to include 12 hallmarks. Every serious longevity company, supplement, and protocol now references these categories.

Most explanations of the hallmarks read like a grad school textbook. I'm going to try to make them actually understandable.

1. Genomic instability

Your DNA accumulates damage over time. UV radiation, toxins, metabolic byproducts, and simple copying errors during cell division all create mutations. Your body has repair machinery (PARP enzymes, sirtuins) that fix most of this damage, but the repair systems slow down with age. The errors pile up.

Cancer risk increases with age not because old people suddenly "get" cancer, but because their DNA has accumulated enough errors that the probability of a cancerous mutation crossing the threshold goes up every year.

NMN, SIRT6 activators, and resveratrol all support DNA repair pathways. That's why they show up in longevity stacks like the DoNotAge sachet.

2. Telomere attrition

Telomeres are protective caps on the ends of your chromosomes. Every time a cell divides, the telomeres get a little shorter. When they get too short, the cell either dies or becomes senescent (stops dividing but doesn't die, just sits there causing problems).

Telomere length is one of the most common biomarkers of biological age. Shorter telomeres correlate with higher disease risk and earlier mortality in population studies.

SIRT6 directly protects telomeres. It's one of the reasons the DoNotAge SIRT6 Activator is their flagship ingredient.

3. Epigenetic alterations

Your DNA sequence doesn't change much over your lifetime. But the chemical tags that control which genes get turned on and off (methylation, histone modifications, chromatin remodeling) shift dramatically with age. Genes that should be active get silenced. Genes that should be silent get activated.

Epigenetic clocks measure this drift. Tests like GrimAge and TruDiagnostic look at methylation patterns across your genome to calculate a biological age separate from your chronological age. TMG supports methylation. Ca-AKG influences both methylation and demethylation.

4. Loss of proteostasis

Your cells make proteins constantly. Some of those proteins misfold or become damaged. Healthy cells have systems (autophagy, the proteasome) that clean up the damaged proteins. When those cleanup systems falter, misfolded proteins accumulate. Alzheimer's amyloid plaques are the most famous example of this failure.

Spermidine activates autophagy, which is the cell's primary method of clearing protein debris.

See also: Spermidine and autophagy: what happens at the cellular level

5. Disabled macroautophagy

Autophagy (literally "self-eating") is how cells recycle their own damaged components. Young cells are aggressive about this. Older cells are not. When autophagy slows down, cellular garbage accumulates. Damaged mitochondria stick around producing excess free radicals. Misfolded proteins pile up.

Fasting activates autophagy. So does spermidine supplementation. Periodic fasting shows longevity benefits in animal models partly through this mechanism.

6. Deregulated nutrient sensing

Your body has pathways that detect nutrient availability and adjust metabolism accordingly. The big ones are mTOR, AMPK, insulin/IGF-1 signaling, and sirtuins. When these pathways lose their calibration with age, you get insulin resistance, chronic inflammation, and metabolic dysfunction.

Berberine activates AMPK. NMN supports sirtuin activity via NAD+. Caloric restriction works partly by modulating these nutrient-sensing pathways.

7. Mitochondrial dysfunction

Mitochondria are the energy factories in your cells. They produce ATP, the molecule your body runs on. With age, mitochondria become less efficient and produce more reactive oxygen species (free radicals) as a byproduct. Damaged mitochondria that should be recycled stick around because autophagy has slowed.

CoQ10 supports mitochondrial electron transport chain function. NMN boosts NAD+, which mitochondria need for energy production. Sulforaphane activates your body's internal antioxidant defenses (the Nrf2 pathway) to manage the increased oxidative stress.

See also: CoQ10 and mitochondrial function after 40

8. Cellular senescence

Senescent cells have stopped dividing but refuse to die. They sit in your tissues and secrete inflammatory molecules (called the SASP, or senescence-associated secretory phenotype) that damage neighboring healthy cells. They're sometimes called "zombie cells" because they're not alive in any productive sense but they're not dead either.

Senolytics are compounds that selectively kill senescent cells. Fisetin and quercetin are the two most studied natural senolytics. Research at the Mayo Clinic has shown that clearing senescent cells extends healthspan in mice.

See also: Senolytic supplements: what zombie cells are and how to clear them

9. Stem cell exhaustion

Your body maintains pools of stem cells that replenish tissues as old cells die. With age, these pools shrink and the remaining stem cells become less effective at producing new cells. Wounds heal slower. Hair thins. Muscle recovery takes longer.

NAD+ appears to support stem cell function. Studies in mice show that boosting NAD+ with NMN rejuvenates aged stem cells.

10. Altered intercellular communication

Cells talk to each other through signaling molecules. With age, this communication breaks down. Chronic low-grade inflammation (sometimes called "inflammaging") is the most common result. The immune system becomes simultaneously overactive (chronic inflammation) and less effective (immunosenescence).

Quercetin, sulforaphane, and omega-3 fatty acids all have anti-inflammatory properties that address this hallmark.

11. Chronic inflammation (added 2023)

Inflammation got its own hallmark in the 2023 update because the research community recognized it's not just a symptom of other hallmarks but a driver of aging in its own right. Chronic inflammation damages tissues, accelerates telomere shortening, promotes senescence, and disrupts metabolism.

Your hs-CRP blood marker is the most accessible way to measure systemic inflammation.

12. Dysbiosis (added 2023)

Also added in 2023. The composition of your gut microbiome changes with age, typically losing diversity and gaining pro-inflammatory species. Gut health influences immune function, nutrient absorption, inflammation, and brain health through the gut-brain axis.

Probiotics, fiber intake, and compounds like berberine (which has antimicrobial properties that may reshape gut flora) address this hallmark.

Why the hallmarks of aging matter for supplement choices

Every longevity supplement targets one or more of these 12 hallmarks. When someone sells you NMN, they're targeting hallmarks 1, 6, 7, and 9. When someone sells you fisetin, they're targeting hallmark 8. When DoNotAge says their sachet "targets all 12 hallmarks of aging," they mean the 15 ingredients collectively cover the full list.

Knowing the framework helps you evaluate any supplement, protocol, or intervention. If someone can't tell you which hallmark their product addresses, they probably don't understand what they're selling.

See also: DoNotAge sachet review: all 15 ingredients

Frequently asked questions