Normal Biologic Changes Associated with Aging
Aging represents a progressive decline in homeostatic resilience mechanisms coupled with accumulation of cellular and molecular damage, manifesting as genomic instability, epigenetic alterations, mitochondrial dysfunction, and reduced compensatory capacity across all organ systems. 1
Fundamental Mechanisms of Biological Aging
Damage Accumulation vs. Resilience Decline
Aging results from two interrelated processes that operate throughout the lifespan 1:
- Accumulated damage (entropic forces): Progressive accumulation of molecular and cellular damage that overwhelms repair mechanisms 1
- Declining resilience mechanisms (homeostatic mechanisms): Early in life, compensatory mechanisms are highly effective and provide robust homeostasis, but these begin to fade later in life, allowing unrepaired damage to accumulate beyond functional thresholds 1, 2
- Clinical manifestation: Damage only emerges clinically when compensatory mechanisms are exhausted, explaining why functional decline accelerates in later life 1
The extreme variability in how these mechanisms maintain homeostasis explains why aging phenotypes vary widely between individuals, even at extreme old age 1
Cellular and Molecular Hallmarks
Genomic Instability
- Somatic mutation accumulation: DNA damage accumulates with age in multiple cell types including B lymphocytes, skeletal muscle satellite cells, and neurons 1
- Functional relevance uncertain: While somatic mutations accumulate from 4 months to 82 years of age, their direct contribution to aging phenotypes remains unclear 1
- DNA repair capacity decline: Quantification of DNA repair capacity in humans remains unsatisfactory, with no consensus on gold standard assays 1
Epigenetic Alterations
DNA methylation changes follow a predefined pattern across individuals and populations, serving as one of the most robust biomarkers of biological aging 1:
- Epigenetic clocks: Methylation at specific CpG sites tracks closely with chronological aging and has been validated across tissues, individuals, and populations 1
- Adaptive response theory: Epigenetic changes represent continuous tuning of gene expression in response to environmental stress throughout the life course 1
- Early-life programming: Massive epigenetic changes occur when environmental stressors (such as food scarcity) are present early in life, and these changes may remain even when conditions improve, contributing to chronic diseases later 1
- Predictive value: "Epigenetically older" individuals have higher risk of age-related diseases, premature mortality, cardiovascular disease, and associations with inflammation and functional decline 1
- Second-generation clocks: PhenoAge and GrimAge indices are strongly predictive of mortality, disability, and dementia 1
Mitochondrial Dysfunction
- Energy production decline: Oxidative phosphorylation capacity declines with aging in heart, skeletal muscle, and other tissues 1
- Functional consequences: Reduced mitochondrial function is associated with mobility decline in older persons, mediated by reduction in muscle strength 1
- Measurement limitations: Current assessment methods (P31 MRS and muscle biopsies) have significant practical limitations for population studies 1
Cardiovascular System Changes
Structural and Biochemical Modifications
- Vascular stiffening: Arteries accumulate lipids, collagen, and minerals, leading to increased vascular stiffness, particularly when atherosclerosis is present 3, 4
- Endothelial dysfunction: Aging alters endothelial cells, reducing endothelium-dependent relaxations and vasodilation responses to beta-adrenoceptor agonists 4
- Cardiomyocyte loss: Progressive loss of cardiomyocytes reduces adaptive capacity and cardiovascular function 3
- Calcium regulation alterations: Vascular calcium regulation is altered, with increased extracellular calcium dependence of contractile responses 4
Autonomic Nervous System Dysregulation
- Noradrenaline elevation: Plasma noradrenaline levels increase with age, primarily due to reduced sensitivity of presynaptic alpha-2 adrenoceptors and decreased noradrenaline uptake 4
- Loss of ANS regulation: Gradual loss of autonomic nervous system regulation contributes to cardiovascular homeostasis disruption 3
Cerebrovascular Changes
- Reduced cerebral perfusion: Regional cerebral blood flow may be reduced in elderly individuals, leading to deterioration of mental and physical functions 4
- Hypertension synergy: The degree of deterioration increases when aging is associated with hypertension 4
Systemic Consequences
Multimorbidity and Disease Susceptibility
The underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability 1:
- Multiple chronic diseases: Most older individuals are affected by multiple chronic diseases, leading to complex treatments and increased risk of physical and cognitive disability 1
- Accelerated aging patterns: Different patterns of multimorbidity emerge due to specific combinations of genetic susceptibility and environmental stress 1
- Disease clustering: Strong correlations exist between aging mechanisms (autophagy, mitochondrial function, cellular senescence, DNA methylation) and health dimensions 1
Functional Decline
- Physical decline: Results from interaction between damage-inducing and damage-preventing mechanisms 1
- Cognitive decline: Follows similar patterns of accumulated damage exceeding compensatory capacity 1
- Frailty: Defined as reduction of physiological compensation, emerging when compensatory mechanisms are exhausted 1
Clinical Implications
Mortality Risk
- Age 28 threshold: After approximately age 28, the inherent aging process becomes the major risk factor for disease and death in developed countries 5, 6
- Exponential increase: The remaining 98-99% of cohorts die at an exponentially increasing rate determined by the aging process 6
- Maximum lifespan: The aging process ensures few reach 100 years and none exceed approximately 122 years 5, 6