Cellular Aging Mechanisms

• People age at a cellular level. Their cells age and decline in functional activity, which can result in degenerative, metabolic, and neoplastic disorders.

Mechanisms of Cellular Aging

• Aging mechanisms can be caused by accumulations of DNA mutations, which occur naturally or are enhanced by reactive oxygen species causing gene mutations.
• Decreased cell replication can also cause aging.
• Abnormal protein homeostasis, resulting in loss of normal proteins or accumulation of misfolded proteins, can cause cell injury and lead to apoptosis.
• Environmental mutagens are substances which cause changes (mutations) in the DNA, leading to genetic alterations that contribute to aging and cancer.
• Reactive oxygen species (ROS) are molecules containing oxygen, generated naturally during cellular processes but increased by environmental stressors like pollution and UV radiation.
• Environmental mutagens can increase the generation of ROS in cells, and ROS can damage DNA directly, leading to base modifications, strand breaks, and crosslinking of DNA strands.
• Environmental mutagens provoke inflammation, causing inflammatory cells to release ROS, which can cause damage to normal tissues in the body.
• Accumulation of ROS-induced DNA damage over time can contribute to mutation accumulation, triggering oncogenes or inactivating tumor suppressor genes.
• Cells have repair mechanisms to fix oxidative DNA damage caused by ROS, but chronic exposure to environmental mutagens and increased ROS levels can overwhelm these repair systems.

Role of Telomeres and Telomerase

• Telomeres are short DNA repeat sequences protecting the ends of chromosomes from degradation.
• Telomerase are RNA protein complexes that add nucleotides to chromosomal ends using RNA as a template.
• With age, somatic cells and stem cells experience telomere shortening due to repeated cell divisions, while cancer cells may increase telomere length to proliferate.
• Shortened telomeres lead to cell cycle arrest and activation of DNA damage response, which results in cell death.

Contributing Causes of Cellular Aging

• Environmental and metabolic insults, telomere shortening, and abnormal protein homeostasis can contribute to decreased cell function and cell loss.

Ways to Slow Cellular Aging

• Increased physical activity and caloric restriction, which decreases signaling pathways, alters transcription, increases DNA repair, improves protein homeostasis, and prolongs cell life, can slow cellular aging.

Factors That Accelerate Cellular Aging

• Stressors like chronic inflammation and cytokines and chronic metabolic disorders such as diabetes, Cushing's disease, and increased glucocorticoid levels all cause DNA damage that promotes accelerated aging.

Clinical Correlations of Cellular Aging

• Telomeropathies are conditions that arise due to defects in telomere maintenance.
• Aplastic anemia results from shortened telomeres in hematopoietic stem cells, reducing their ability to divide and produce functional blood cells.
• Premature graying occurs due to telomere attrition in melanocyte stem cells, which leads to a loss of pigment production in hair follicles.
• Skin pigment and nail abnormalities result from telomere shortening in skin and nail cells, impairing their ability to regenerate and maintain skin and nail health.
• Pulmonary and liver fibrosis are associated with telomere dysfunction in fibroblasts, leading to excessive scarring in response to chronic injury or inflammation.

Hutchinson-Gilford Progeria Syndrome

• This is an autosomal dominant mutation in the LMNA gene that leads to a defective progerin protein, which affects the nuclear lamina, destabilizing the nuclear architecture and leading to rapid cell aging.
• Clinical signs of this syndrome include delayed growth, alopecia, and cardiovascular disease. Affected individuals often die in their teens due to cardiovascular complications, and they may also experience skeletal, joint, and connective tissue issues.
• The LMNA gene encodes lamin A and lamin C, components of the nuclear lamina which maintain the structural integrity of the nucleus and ensures proper DNA and cell division.
• In HGPS, an autosomal dominant mutation occurs in the LMNA gene, leading to the production of progerin, a defective form of lamin A which causes instability in the nuclear envelope and disrupts nuclear lamina.
• The disruption of the nuclear lamina by progerin causes accelerates cellular aging by causing genomic instability, defective DNA repair, increased oxidative stress and premature cell death.
• Children with HGPS show signs of delayed growth starting around 6-12 months and have short stature as they age.
• Alopecia is a common feature in HGPS due to the failure of hair follicle stem cells to function properly.
• One of the most severe aspects of HGPS is the early onset of cardiovascular disease, particularly heart failure or stroke.
• Individuals with HGPS often experience skeletal abnormalities such as osteoporosis, hip dislocation, and joint stiffness.

Nuclear Lamina and Cell Cycle

• The nuclear lamina maintains nuclear structure and regulates DNA.
• Disruptions in the lamina, such as in progeria, cause genomic instability and accelerates aging.

Future Career in Geriatric Medicine

• The population is aging, making geriatric medicine an important and lucrative career for doctors.