The 12 hallmarks of aging
The 12 hallmarks of aging are a set of biological processes that describe how organisms age at a molecular and cellular level. First proposed as nine hallmarks in 2013 and expanded to twelve in a landmark 2023 update, these mechanisms fulfill three criteria:
- they manifest during normal aging,
- their experimental aggravation accelerates aging, and
- their amelioration can delay it¹
They are typically grouped into three functional categories:
1. Primary Hallmarks (The Triggers)
These are the root causes of cellular damage that accumulate over time.
- Genomic Instability: The accumulation of DNA damage from internal (metabolic) and external (radiation, toxins) stressors that the body can no longer perfectly repair.
- Telomere Attrition: The shortening of protective caps at the ends of chromosomes; once they become too short, cells stop dividing or die.
- Epigenetic Alterations: Changes in how genes are "read" without altering the DNA sequence itself, often leading to beneficial genes being turned off or harmful ones turned on.
- Loss of Proteostasis: The failure of quality control systems that ensure proteins are correctly folded and recycled, leading to "cellular clutter" linked to diseases like Alzheimer’s.
- Disabled Macroautophagy: The breakdown of the cell’s internal recycling system, which normally clears out damaged organelles and debris.
2. Antagonistic Hallmarks (The Responses)
These processes are initially beneficial (e.g., to prevent cancer) but become detrimental when they become chronic with age.
- Deregulated Nutrient-Sensing: Pathways like insulin and mTOR lose their sensitivity, disrupting metabolism and energy management.
- Mitochondrial Dysfunction: A decline in the efficiency of cellular power plants, leading to less energy production and increased “leaks” of damaging reactive oxygen species.
- Cellular Senescence: Damaged cells that stop dividing but remain metabolically active, secreting inflammatory signals that affect surrounding tissue.
3. Integrative Hallmarks (The Consequences)
These represent the final functional decline at a tissue and systemic level.
- Stem Cell Exhaustion: The depletion of the body’s repair systems, reducing the ability of tissues to regenerate.
- Altered Intercellular Communication: Disrupted signalling between cells, contributing to hormonal imbalance and immune dysfunction.
- Chronic Inflammation: Often referred to as “inflammaging,” this persistent low-level inflammation contributes to most chronic diseases.
- Dysbiosis: An imbalance in the gut microbiome that can trigger systemic inflammation and influence metabolic and immune function.
Footnotes
- Hallmarks of aging: An expanding universe https://pubmed.ncbi.nlm.nih.gov/36599349/
