The progressive decline in physiological function and increased vulnerability to disease and death over time. Biological aging involves accumulation of molecular damage, cellular senescence, mitochondrial dysfunction, inflammation (inflammaging), and loss of regenerative capacity.
Aging involves multiple hallmarks: genomic instability (DNA damage accumulation, telomere shortening), epigenetic alterations (DNA methylation changes), loss of proteostasis (protein misfolding), mitochondrial dysfunction (reduced ATP, increased ROS), cellular senescence (p16/p21 activation, SASP secretion), stem cell exhaustion, altered intercellular communication (inflammaging, immunosenescence), and nutrient sensing dysregulation (insulin/IGF-1, mTOR, AMPK, sirtuins). These processes are interconnected—mitochondrial dysfunction drives inflammation, inflammation drives cellular senescence, senescence drives tissue dysfunction.
Aging is the primary risk factor for chronic diseases (cardiovascular disease, cancer, neurodegeneration, diabetes). cPNI interventions target modifiable aging mechanisms: reducing chronic inflammation (metainflammation), enhancing mitochondrial function (exercise, fasting, hormesis), supporting cellular repair (autophagy, NAD+ repletion), and optimizing hormone function (sex hormones, GH, thyroid). Caloric restriction, time-restricted eating, exercise, and stress management are evidence-based interventions.
- Primary risk factor for cancer, cardiovascular disease, neurodegeneration, diabetes
- Telomere shortening: ~50-100 bp lost per cell division; <5 kb triggers senescence
- Inflammaging: chronic low-grade inflammation (elevated IL-6, TNF, CRP)
- Immunosenescence: thymic involution, T cell repertoire contraction, ↓NK function
- Mitochondrial DNA mutations accumulate with age (0.5-1% per decade)
- Epigenetic aging clocks (Horvath, Hannum) predict biological vs chronological age
- Cellular senescence increases exponentially after age 60
- NAD+ levels decline 50% from age 40 to 80
- Growth hormone and sex hormones decline progressively
- Caloric restriction extends lifespan in multiple species; effects via sirtuins, AMPK, mTOR inhibition
- inflammation — Inflammaging—chronic low-grade inflammation driving aging
- IL-6 — Elevated in aging; marker of inflammaging
- TNF — Elevated in aging; contributes to muscle wasting and inflammation
- mitochondrial dysfunction — Central mechanism of aging; reduced ATP, increased ROS
- cellular senescence — Accumulation of senescent cells drives tissue dysfunction
- telomeres — Telomere shortening limits replicative capacity; marker of biological age
- epigenetics — Epigenetic drift and methylation changes define biological age
- NAD+ — Declines with age; essential for mitochondrial function and sirtuin activity
- sirtuins — NAD+-dependent deacetylases promoting longevity and stress resistance
- autophagy — Declines with age; impairs cellular quality control
- caloric restriction — Most robust intervention extending lifespan across species
- mTOR — Hyperactivation promotes aging; inhibition (via rapamycin/fasting) extends lifespan
- insulin resistance — Develops with aging; contributes to metabolic dysfunction
- growth hormone — Declines with age; contributes to sarcopenia and metabolic changes
- estrogen — Decline in women increases cardiovascular and neurodegenerative risk
- testosterone — Decline in men contributes to sarcopenia, metabolic syndrome, cognitive decline
- immunosenescence — Age-related decline in immune function
- neurodegeneration — Aging is primary risk factor for Alzheimer's and Parkinson's
- exercise — Counteracts aging via mitochondrial biogenesis, autophagy, inflammation reduction
- oxidative stress — Free radical theory of aging; ROS damage accumulates