Review Article| Volume 27, ISSUE 4, P491-506, November 2011

Theories and Mechanisms of Aging

Published:September 23, 2011DOI:
      Several theories may explain the normal aging process, either alone or in combination with other theories (Table 1). These theories can be generally classified into evolutionary, involving historical and evolutionary aspects of aging, and physiologic or structural and functional changes. Processes that may explain these theories at a cellular level include intrinsic timing mechanisms and signals, accidental chance events, programmed genetic signals making an organism more susceptible to accidental events, nuclear or mitochondrial DNA mutations or damage, damaged and abnormal proteins, cross-linkage, glycation, waste accumulation, general molecular wear and tear, free radical formation, and specific cellular components such as gene, chromosome, mitochondria, or telomeres. Physiologic processes that may explain aging include oxidative stress, immunologic, neuroendocrinologic, metabolic, and insulin signaling, and caloric restriction.
      • Pacala J.T.
      • Sullivan Gm
      Geriatric review syllabus: a core curriculum in geriatric medicine.
      Table 1Major cellular and functional changes of aging by prominent theories and major associated clinical disease outcomes
      Organ System Major Theories Cell Level Structural/Functional Changes of Aging Disease Outcomes
      Integumentary Oxidative stress; free radical; genetic; autoimmune Melanocytes, mast, and Langerhans cells Thinning of stratum corneum and subcutaneous layer Squamous and basal cell carcinoma; malignant melanoma
      Oral Oxidative Stress; free radical; genetic; autoimmune Buccal Increased thickness of tooth dentin, decreased dental pulp; thinning of oral mucosa and receding of gums; decreased sensitivity for smell and taste Squamous cell carcinoma; tooth decay
      Visual Oxidative stress; free radical; genetic Rods and cones Reduced night vision, accommodative ability and increased glare Macular degeneration; cataracts; diabetic retinopathy
      Hearing Oxidative stress; free radical; genetic Sensory and neural cells Stiffening of the inner ear bones Presbycusis; osteosclerosis
      Musculoskeletal Oxidative stress; genetic; autoimmune Myocytes Apoptosis, reduced size of myofibrils, decreased type 2 muscle fibers; decreased hand grip strength with more in the lower extremities Falls; disuse atrophy; chronic musculoskeletal disorders
      Skeletal Oxidative stress; free radical; neuro endocrine Osteoblasts and osteoclasts Change in bone architecture and accumulation of microfractures, disparity in the concentration of deposited minerals, changes in the crystalline properties of mineral deposits and protein content of the matrix; decreased height and thinning of bone Fractures
      Cardiovascular Oxidative stress; free radical; neuroendocrine; genetic Myocyte; pacemaker cell Increase in left ventricular stiffness and decrease in compliance; decreased left ventricular diastolic filling and relaxation, increased stroke volume, reduction in maximal cardiac output and vasodilator response to exercise Congestive heart failure; cardiomyopathy; heart block
      Pulmonary Oxidative stress; free radical; genetic; autoimmune Alveolar cells Chest wall stiffness; decreased arterial oxygenation and impaired carbon dioxide elimination; decrease in vital capacity and forced expiratory volume, increased residual volume and functional residual capacity Chronic lung disease; carcinoma
      Gastrointestinal Oxidative stress; free radical Mucosal cell Decreased elasticity of connective tissue; reduction in phase I metabolism Carcinoma; increased risk of drug–drug and drug–disease interactions
      Renal/urogenital Oxidative stress; free radical; genetic; neuroendocrine; autoimmune Renal cell Diminished proliferative reserve; apoptosis; loss of glomerular and tubular mass; decline in GFR, loss of tubular volume and narrowed homeostatic control of water and electrolyte balance Carcinoma; chronic renal failure
      Neurologic Oxidative stress; free radical; genetic; neuroendocrine Neurons; glial cells Decrease in size of hippocampus and frontal and temporal lobes; decreased number of receptors of all types in the brain with increased sensitivity; decrease in complex visuoconstructive skills and logical analysis skills; decrease in processing speed, decrease in reaction time and decrease ability to shift cognitive sets rapidly; memory distraction and decline in executive function; abnormal reflexes Neuropathy; neurodegenerative disorders
      Hematologic Autoimmune; genetic; oxidative stress; free radical Stem cells Decreased marrow cellularity, increase in bone marrow fat and reduction in cancellous bone Chronic anemia; myelofibrosis; leukemia
      Neuroendocrine Neuroendocrine; oxidative stress; genetic Neuroendocrine cells; mitochondria Decrease or increase in hormone levels; inability to conserve or dissipate heat Autonomic neuropathy; thyroid disease; adrenal insufficiency; male and female menopause


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