Week 9 A - Life and Death of Cells and Organisms

Understanding Factors Affecting Cell Lifespan and Aging

• There are various factors impacting the lifespan of cells which can also affect aging processes.

  • Key Factors Include:

  • Telomere length

  • DNA damage and repair systems

  • Energy levels and metabolism

  • Signaling pathways (e.g., Insulin/IGF, PI3K, Tor, Sirtuins)

  • Autophagy (self-eating)

Aging and Longevity

• Aging cannot be reversed; however, understanding the processes involved can help extend healthy lifespan.

• Concept of Subclinical Aging:

  • Subclinical aging refers to biological degeneration that does not show outward symptoms but affects biological functioning.

  • Progression involves chronic disease and aging-related deterioration that can determine life expectancy.

Cellular Changes Associated with Aging

• Hematopoietic Stem Cells (HSC):

  • Changes in the bone marrow microenvironment that affect cellular metabolism and hematopoietic reconstitution.

• Innate Immune Cells (e.g., Dendritic Cells, Macrophages, Neutrophils):

  • Exhibit defective homing capabilities and a decreased ability to uptake antigens.

  • Increased production of inflammatory cytokines, decreased reactive oxygen species (ROS) production, and reduced bactericidal function.

• Adaptive Immune Cells (T Cells and B Cells):

  • Show reduced cytolytic potential, impaired response to cytokines like IL-2, and reduced antibody affinity.

Proliferation of Cells

• Cells vary in their ability to grow and divide:

  • Post-mitotic cells do not divide (e.g., nerve cells, erythrocytes).

  • Stem cells continue to divide throughout life (e.g., intestinal epithelium).

  • Quiescent Cells: Remain dormant but can be activated to divide when necessary (e.g., liver cells after injury).

Importance of Cellular Turnover

• Human Cell Replacement Rates:

  • Different cell types have distinct turnover times:

  • Small intestine epithelium: 2-4 days

  • Stomach lining: 2-9 days

  • Neutrophils: 1-5 days

  • Overall cell turnover rates diminish with age, influencing tissue functionality and repair ability.

Telomere Length and Telomerase Activity

• Telomerase:

  • Enzyme that maintains telomere length, affecting cell division potential.

  • Insufficient telomerase leads to senescence limiting cell divisions, which is a critical factor in aging and tumor suppression.

• Telomere Exhaustion:

  • Cells expressing low telomerase can become senescent, leading to chromosomal instability and apoptosis.

DNA Damage and Repair Mechanisms

• Types of Damage:

  • Single and double-strand breaks, base, mismatch, and nucleotide excision.

  • Damage can result from environmental factors (radiation, chemicals) or natural biological processes (replication errors).

• DNA Repair Processes:

  • Base excision repair, mismatch repair, and nucleotide excision repair are vital in maintaining genomic stability.

The Role of Autophagy

• Definition:

  • Autophagy is a process where cells degrade and recycle cellular components to maintain cellular health, especially under stress conditions.

  • Essential for energy and redox homeostasis, it can mitigate aging effects.

• Pathological Implications:

  • Autophagy is linked to various diseases like neurodegenerative diseases, type II diabetes, and cancer.

Signaling Pathways Influencing Aging

• Insulin/IGF Signaling:

  • Key for metabolic regulation; chronic food restriction can downregulate pathways, promoting longevity.

• mTOR Pathway:

  • Higher mTOR activity is associated with growth and aging; its inhibition through caloric restriction promotes lifespan extension (e.g., Rapamycin).

Summary

• Several factors influence aging at the cellular level:

  • Telomerase activity, DNA damage repair systems, metabolic energy levels, and signaling pathways (Insulin/IGF, mTOR) are crucial targets to potentially mitigate aging processes.

  • Autophagy plays a significant role in maintaining cellular integrity, providing opportunities for interventions aimed at extending healthspan.