Are these 18 things all that's killing you?
Here is a list of the known reasons for aging, combining 12 of the best-supported1 with 6 additional emerging factors that are under investigation (and what you can do about each):
1. Genomic Instability
Accumulation of DNA damage over time, leading to mutations and loss of cellular function.2
Interventions:
Antioxidants: Vitamin C, Vitamin E, CoQ10, and polyphenols (e.g., resveratrol) may help reduce oxidative damage to DNA.
DNA repair enhancers: NAD+ precursors (e.g., Nicotinamide Riboside, NMN) promote DNA repair by boosting sirtuin activity.
Minimizing environmental toxins: Reduce exposure to pollutants, UV radiation, and avoid smoking.
2. Telomere Attrition
Progressive shortening of telomeres, limiting cellular division and contributing to aging.3
Interventions:
Telomerase activators: TA-65 and astragalus extract may help extend telomere length.
Exercise: Aerobic exercise and resistance training are shown to preserve telomere length.
Meditation: Mindfulness and stress-reducing activities can slow telomere shortening.
3. Epigenetic Alterations
Changes in gene expression without altering the DNA sequence, affecting aging-related gene regulation.4
Interventions:
Dietary modulation: Caloric restriction, fasting, and ketogenic diets influence epigenetic markers.
Sirtuin activators: Resveratrol, pterostilbene, and NAD+ precursors promote beneficial epigenetic modifications.
Exercise: Physical activity promotes beneficial changes in gene expression related to aging.
4. Loss of Proteostasis
Decline in the maintenance of properly folded proteins, leading to accumulation of damaged proteins.5
Interventions:
Heat shock proteins (HSP) activators: Sauna therapy or heat stress increases HSPs, which help repair misfolded proteins.
Autophagy boosters: Fasting and caloric restriction enhance autophagy, clearing damaged proteins.
Proteostasis enhancers: Curcumin and spermidine are shown to support proteostasis.
5. Mitochondrial Dysfunction
Reduced efficiency in mitochondrial energy production, causing cellular decline.6
Interventions:
Mitochondrial support supplements: CoQ10, PQQ, Alpha Lipoic Acid (ALA), and Acetyl-L-Carnitine.
NAD+ boosting: Supplementing with NAD+ precursors (e.g., Nicotinamide Riboside or NMN) to enhance mitochondrial function.
Exercise: High-Intensity Interval Training (HIIT) and aerobic exercise improve mitochondrial efficiency.
6. Cellular Senescence
Accumulation of cells that can no longer divide or function properly, promoting tissue dysfunction.7
Interventions:
Senolytics: Quercetin, Fisetin, and Dasatinib (used in research settings) can selectively clear senescent cells.
Exercise: Physical activity reduces senescent cell burden.
Fasting: Intermittent fasting and time-restricted eating may promote the clearance of senescent cells.
7. Stem Cell Exhaustion
Depletion of stem cells, reducing the body’s ability to regenerate tissues.8
Interventions:
Stem cell rejuvenation therapies: Mesenchymal stem cell infusions (experimental).
Fasting: Prolonged fasting may stimulate stem cell regeneration, especially in the immune system.
NAD+ precursors: Support stem cell maintenance through mitochondrial health.
8. Deregulated Nutrient Sensing
Impairment in nutrient-sensing pathways (e.g., mTOR, AMPK), contributing to metabolic dysregulation and aging.9
Interventions:
Caloric restriction: Proven in multiple species to enhance longevity by affecting nutrient-sensing pathways like mTOR and IGF-1.
Metformin: Reduces IGF-1 and mTOR signaling, shown to extend lifespan in animal models.
AMPK activators: Berberine and ALA activate AMPK, promoting longevity.
9. Altered Intercellular Communication
Disruption in the signaling between cells, leading to chronic inflammation and tissue degradation.10
Interventions:
Anti-inflammatory diet: Rich in omega-3 fatty acids (e.g., fish oil) and antioxidants reduces chronic inflammation.
Intermittent fasting: Reduces pro-inflammatory cytokine levels and promotes healthy intercellular signaling.
Senolytics: Quercetin and Fisetin may reduce the pro-inflammatory signaling from senescent cells.
10. Disabled Macroautophagy
Impairment in the process of cellular clean-up, where damaged organelles and proteins are not properly removed.11
Interventions:
Fasting: Intermittent fasting and extended fasting strongly boost autophagy.
Rapamycin: Inhibits mTOR and enhances autophagy (currently used in research, not widely available).
Polyphenols: Resveratrol and spermidine have been shown to induce autophagy.
11. Chronic Inflammation (Inflammaging)
Persistent, low-grade inflammation that damages tissues and promotes age-related diseases.12
Interventions:
Omega-3 fatty acids: Fish oil supplements have potent anti-inflammatory effects.
Anti-inflammatory compounds: Curcumin, ginger, and green tea extract reduce inflammation.
Regular exercise: Physical activity reduces systemic inflammation markers.
12. Accumulation of Cellular Damage
Gradual accumulation of cellular damage from oxidative stress, radiation, and other metabolic by-products.13
Interventions:
Antioxidants: Supplementing with Vitamin C, E, glutathione, and alpha-lipoic acid can reduce oxidative damage.
Mitochondrial support: CoQ10, PQQ, and NAD+ precursors help combat oxidative stress.
Sauna therapy: Induces heat shock proteins, which repair cellular damage.
Emerging Factors:
13. Microbiome Alterations
Changes in the gut microbiota composition that influence systemic inflammation, immune response, and metabolism.14
Interventions:
Probiotics: Specific strains (e.g., Lactobacillus, Bifidobacterium) can improve gut health.
Prebiotics: Dietary fibers such as inulin and resistant starches support a healthy microbiome.
Diet: A plant-rich diet high in fiber and fermented foods improves microbiome diversity.
14. Circadian Rhythm Disruption
Disruptions in the body’s internal clock, affecting metabolic and immune processes, potentially accelerating aging.15
Interventions:
Consistent sleep schedule: Maintaining regular sleep-wake cycles is essential for circadian health.
Light exposure: Morning sunlight exposure supports healthy circadian rhythms.
Melatonin: Supplementation can help regulate sleep cycles and improve circadian rhythm alignment.
15. Immune System Dysregulation (Immunosenescence)
The weakening of the immune system with age, reducing the body’s ability to fight infections and control inflammation.16
Interventions:
Vitamin D: Supports immune function and helps regulate immune responses.
Zinc: Plays a crucial role in immune system regulation and may help combat immunosenescence.
Moderate exercise: Regular, moderate-intensity exercise boosts immune function and reduces inflammation.
16. Metabolic Waste Accumulation (e.g., Lipofuscin)
Accumulation of metabolic by-products such as lipofuscin, leading to impaired cellular function and tissue aging.17
Interventions:
Autophagy inducers: Fasting and caloric restriction help clear cellular debris and lipofuscin.
Spermidine: Promotes autophagy and may reduce metabolic waste accumulation.
Sauna therapy: Increases heat shock proteins, which can help clear cellular waste.
17. Glycation and Advanced Glycation End-Products (AGEs)
Formation of AGEs through the glycation of proteins and lipids, contributing to tissue damage and aging-related diseases.18
Interventions:
Low-glycemic diet: Reducing sugar and refined carbohydrates lowers AGEs in the body.
Alpha-lipoic acid (ALA): Shown to reduce glycation and AGE formation.
Carnosine: A supplement that can inhibit the formation of AGEs.
18. Caloric Overload and Nutrient Excess
Chronic over-nutrition contributing to metabolic overload, oxidative stress, and insulin resistance, which may accelerate aging.19
Interventions:
Caloric restriction: Proven to reduce metabolic overload and extend lifespan in animal studies.
Fasting: Periodic fasting reduces excess nutrient load and promotes metabolic flexibility.
Exercise: Regular physical activity helps balance energy metabolism and reduce excess nutrient storage.
This list represents a comprehensive view of the known biological mechanisms and emerging factors contributing to aging. While the first 12 are strongly established in empirical research, the final 6 are under ongoing investigation and may gain further support as our understanding of aging evolves (or may fall off the list). As significant new information becomes available, I expect to update and republish this post. So, stay tuned.
The Hallmarks of Aging - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/
Causes of genome instability: the effect of low dose chemical exposures in modern society - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565613/
Telomeres, lifestyle, cancer, and aging - https://pubmed.ncbi.nlm.nih.gov/21102320/
Epigenetic alterations—The silent indicator for early aging and age‐associated health‐risks - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9805292/
The Biology of Proteostasis in Aging and Disease - https://www.annualreviews.org/content/journals/10.1146/annurev-biochem-060614-033955
Mitochondrial dysfunction: mechanisms and advances in therapy - https://www.nature.com/articles/s41392-024-01839-8
Cellular senescence in ageing: from mechanisms to therapeutic opportunities - https://www.nature.com/articles/s41580-020-00314-w
Stem Cell Exhaustion - https://link.springer.com/chapter/10.1007/978-3-031-55022-5_7
Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease - https://pubmed.ncbi.nlm.nih.gov/30779006/
Altered Intracellular Communication: Hallmark of Aging #9 - https://oxfordhealthspan.com/blogs/aging-well/altered-intracellular-communication-hallmark-of-aging-9
Macroautophagy and aging: The impact of cellular recycling on health and longevity - https://www.sciencedirect.com/science/article/pii/S0098299721000807
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty - https://www.nature.com/articles/s41569-018-0064-2
Cell Damage and Transformation in Aging - https://link.springer.com/referenceworkentry/10.1007/978-3-030-22009-9_434
The Gut Microbiota and Inflammation: An Overview - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589951/
The wrinkling of time: Aging, inflammation, oxidative stress, and the circadian clock in neurodegeneration - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727873/
Aging of the Immune System. Mechanisms and Therapeutic Targets - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291468/
Lipofuscin: mechanisms of age-related accumulation and influence on cell function - https://pubmed.ncbi.nlm.nih.gov/12208347/
Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029922/
Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe? - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678135/