Telomerase and Aging

What happens when telomeres reach critically short lengths in cells without telomerase?

Cells stop proliferating and enter permanent / irreversible cell cycle arrest (cell senescence).

senescence can act as __________

tumor suppression mechanism

Hayflick limit is

maximum number of times a normal somatic cell can divide before it stops dividing and enters a state of cellular senescence.

• a form of cellular aging

immortal cell have

high telomerase activity that maintains telomere length allowing unlimited divisions and preventing senescence

Telomere length and telomerase activity___________

varies in different cell types of an organism

Embryonic and pluripotent stem cells have

high telomerase activity → maintain telomere length

• Embryonic Stem Cells (ESCs): Found in the inner cell mass of a blastocyst during early embryonic development.

• Induced Pluripotent Stem Cells (iPSCs): Somatic cells reprogrammed to a pluripotent state in vitro.

• Germ Cells: Precursors to sperm and eggs, maintaining high telomerase activity to protect telomeres for reproductive purposes.

Tissue Stem Cells have

medium telomerase activity → gradual decrease in telomere length

• Hematopoietic Stem Cells (HSCs): Found in the bone marrow, responsible for generating blood cells.

• Mesenchymal Stem Cells (MSCs): Found in various tissues like bone marrow, fat, and umbilical cord, involved in tissue repair.

• Satellite Cells: Muscle stem cells that aid in muscle repair and regeneration.

Telomerase Activity:

embryonic and pluripotent stem cells → high telomerase activity to maintain indefinite proliferation

tissue stem cells → lower telomerase activity to balance repair and cancer suppression.

Progenitor and differentiated cells → typically exhibit negligible telomerase activity, leading to gradual telomere shortening and eventual senescence.

progenitor and differentiated cells have

low/absent telomerase activity → senescence

Differentiated Cells / Specified Cells (progenitor)

• Fibroblasts: Cells that produce collagen and extracellular matrix in connective tissues.

• Keratinocytes: Skin cells forming the epidermis, with limited capacity for division.

• Hepatocytes: Liver cells with some regenerative ability but low telomerase activity.

Senescence of tissue stem cells may contribute to __________

aging

TERC mRNA of telomere knockout result in

defects in tissue homeostasis

• infertility increases with generation → germ line stem cell apoptosis

• Diskeratosys Congenita like phenotypes: due to limited tissue stem cell proliferation

other disease due to poor telomere maintenance / premature aging

• defective closure of neural tube

• small size / atrophy of the intestine

• abnormal skin pigmentation

• defective skin/nail/hair regeneration

• bone marrow failure

• death

TERT (protein component) Over expressed Mice

• Live longer

• higher incidence of cancer

  • revealed that balance between cancer and telomere length

What factors, aside from telomerase and telomere length, contribute to organismal aging?

• Epigenetic changes and spurious transcription.

• Accumulation of mutations due to replication errors and other challenges.

• Changes in the extracellular matrix (ECM) or cellular composition of the stem cell niche.

• Altered signals disrupting cell-cell communication.

• Endocrine signals (e.g., differences between young and old blood).

What role do circulatory factors play in aging and stem cell decline?

Circulatory factors, including endocrine signals, affect the systemic environment:

• Aging blood introduces inflammatory and immune factors that impair stem cell function.

• Young blood provides rejuvenating factors that promote regeneration.

What are the primary hallmarks of aging and their impact?

cause cellular damage:

• Genomic instability (mutations)

• Telomere attrition (shortening of telomeres)

• Epigenetic alterations (modifications to gene expression)

• Loss of proteostasis (protein function)

What are the antagonistic hallmarks of aging, and how do they respond to damage?

responses to damage:

• Deregulated nutrient-sensing (Metabolic imbalances)

• Mitochondrial dysfunction (Energy deficits)

• Cellular senescence (irreversible arrest of the cell cycle)

What are the integrative hallmarks of aging, and what do they result in?

culminate in aging phenotypes:

• Stem cell exhaustion → decline in the function, number, or regenerative capacity of stem cells over time causing Reduced tissue regeneration, aging, increased disease risk

• Altered intercellular communication (dysregulated signaling) → Inflammaging, impaired tissue function, cancer progression

Telomerase activity process

1. telomerase recognizes the telomere repeat sequence located at the end of chromosomes

2. Telomerase with its integral RNA template adds additional telomere repeats

3. Primer attaches to the added telomere region

4. polymerase alpha completes the lagging strand

Telomere is

Repetitive nucleotide sequence that caps the ends of linear chromosomes → thousands of TTAGGG

• attracts telomerase to the chromosome ends

constitutive heterochromatic (condensed) region that is a devoid of genes

Telomerase is

Enzyme that elongates telomeres, synthesizing the repetitive nucleotide sequences found at the ends of eukaryotic chromosomes.

• carries its own RNA template → used to add multiple copies of the same repetitive DNA sequence to the lagging strand template

DNA polymerase only adds nucleotides to the _______ an existing polynucleotide chain

3’ end

• DNA polymerase can only synthesize DNA from 5’ to 3

What Are Regenerative Tissues?

Cells that require frequent cell turnover or repair to maintain their function throughout life.

• stem cells dependent to replenish lost or damaged cells.

  • Skin

  • Intestinal lining

  • Bone marrow

  • Liver

** NONE OF THESE ARE STEM, IPS, OR GERM CELLS

• These will gradually die

what are proliferating tissues

tissues in which cells are actively dividing (proliferating) to support growth, maintenance, or repair