What Goes Wrong: How the Hallmarks Change with Age

The aging process involves a progressive deterioration in the efficiency and coordination of these twelve hallmarks. Understanding how each changes with age provides insight into why aging affects virtually every aspect of bodily function.

Genomic instability increases exponentially with age due to both increased damage and decreased repair capacity. The rate of somatic mutations in humans increases from about 17 mutations per year at birth to over 47 mutations per year by age 75. This acceleration occurs because DNA repair mechanisms themselves become damaged and less efficient over time. Telomere attrition follows a predictable pattern, with telomeres shortening by approximately 50-100 base pairs per year in most tissues. However, this rate varies significantly between individuals and can be accelerated by stress, poor lifestyle choices, and chronic disease. Some cells, particularly stem cells and certain immune cells, maintain telomerase activity to counteract this process, but even this capacity declines with age. Epigenetic alterations show characteristic patterns with aging. Global DNA methylation tends to decrease, while specific gene promoters become hypermethylated, silencing important genes. The "epigenetic clock" based on methylation patterns can predict biological age with remarkable accuracy, often more precisely than chronological age. Loss of proteostasis manifests as decreased efficiency of protein folding chaperones, reduced proteasome activity, and impaired clearance of protein aggregates. This is particularly problematic in long-lived cells like neurons, where protein aggregates can accumulate for decades. Dysregulated nutrient sensing typically involves decreased insulin sensitivity, altered mTOR signaling, and reduced AMPK activity. These changes make cells less able to respond appropriately to nutrients and stress, contributing to metabolic dysfunction and reduced stress resistance. Mitochondrial dysfunction includes decreased ATP production, increased reactive oxygen species generation, and accumulation of damaged mitochondria. The mitochondrial genome, which lacks the sophisticated repair mechanisms of nuclear DNA, accumulates mutations that impair energy production. Cellular senescence increases dramatically with age, with senescent cell burden doubling approximately every 10 years in humans. These cells secrete over 100 different inflammatory molecules, creating a toxic environment for surrounding healthy cells. Stem cell exhaustion occurs through multiple mechanisms including telomere shortening, DNA damage accumulation, and changes in the stem cell niche. The regenerative capacity of most tissues declines significantly with age, reducing the ability to repair damage and maintain homeostasis. Altered intercellular communication includes changes in hormone production, increased inflammatory signaling, and altered cell adhesion. The endocrine system becomes less coordinated, and chronic inflammation disrupts normal cellular communication. Chronic inflammation develops through multiple pathways including the accumulation of senescent cells, damaged cellular components that trigger innate immune responses, and dysregulated immune system function. This creates a persistent inflammatory environment that accelerates tissue damage. Disabled macroautophagy results from decreased expression of autophagy genes, impaired lysosomal function, and disrupted autophagosome formation. This leads to accumulation of damaged organelles and protein aggregates that further impair cellular function. Compromised autophagy encompasses broader defects in cellular quality control systems, making cells less able to maintain homeostasis and respond to stress.