Molecular Basis of Aging: Metabolism and Genome Integrity

Molecular Basis of Aging: Metabolism and Genome Integrity

• The lecture covers the molecular mechanisms of aging, focusing on metabolism and genome integrity.
• Specific aims include appreciating progeroid syndromes' genetic basis and its connection to accelerated aging.
• Understanding how insulin signaling affects longevity (in Drosophila and C. elegans).
• Learning about telomere shortening and maintenance.
• Exploring the Hayflick limit and its relationship to cellular senescence.

Disruption in Metabolism and Genome Integrity

• Defects in a small set of cellular functions can cause progeroid syndromes.
• Examples include Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Werner syndrome, and others.
• These defects lead to multiple impairments in nuclear integrity, nucleotide excision repair, and metabolism.
• Environmental influences, along with these cellular defects, contribute to aging processes.

Aging as Developmental Biology

• Aging is comparable to developmental biology, where death is the ultimate outcome.
• Research on model organisms (Drosophila, Mus musculus, and Caenorhabditis elegans) provides insights into molecular mechanisms of development and aging.
• A C. elegans mutation can double adult lifespan by altering insulin signaling. This is the opposite of a progeroid syndrome.

Insights from C. Elegans - Dauer Larva

• C. elegans larvae can enter a dauer stage under specific environmental conditions.
• This stage enhances survival in harsh conditions.
• The duration each stage spends can be determined by external factors.

Age-1: A Gene Promoting C. elegans Longevity

• 1988 study identified the age-1 gene mutant as having a link to longer lifespan.
• It increases the post-reproductive adult lifespan by about twofold.
• The age-1 mutant shows a partial loss of function of the wild-type function.

Age-1 and Daf-23 are Allelic

• The age-1 and daf-23 genes code for the same protein, but different alleles.
• daf-23 constantly produces the dauer larval form, even when ample food is present.
• Well-fed age-1 mutants are long-lived as adults, in contrast to the wild type.

Dauer Formation is Regulated by the Insulin Signaling Pathway

• Insulin stimulates glucose uptake from the blood and converts it to glycogen.
• It also increases fatty acid synthesis, which results in the lipid esterification and fat production within adipose tissue.
• Insulin signaling's effects depend on environmental factors such as caloric intake. This path is important for aging processes.

Insulin Signaling Is Highly Conserved

• Insulin signaling pathways are conserved between mammals and C. elegans.
• Mammalian signaling is regulated by Insulin Receptor and IGF-1 Receptor.
• C. elegans employs DAF-2, AGE-1, DAF-18, AKT, DAF-16.

Reduced Insulin Signaling and Longevity

• C. elegans daf-16 mutants and loss-of-function mutations significantly increase lifespan.
• A complete absence of daf-16 yields constitutive dauer larva formation and a decreased lifespan.

Downstream Targets of DAF-16

• DAF-16 has downstream targets crucial for longevity.
• These targets include antioxidants, small heat-shock proteins (HSPs), antimicrobial peptides, and new genes.

Summary of Insulin Signaling and Longevity

• Caloric restriction accelerates dauer formation in C. elegans.
• Partial caloric restriction extends lifespan.
• Mutated genes regulating insulin signaling affect lifespan.
• Similar genes promote lifespan in Drosophila.

For Humans, Insulin Signaling and Longevity:

• Complete inhibition of insulin signaling is harmful in humans.
• Caloric restriction as a human longevity strategy is still uncertain.
• Obesity correlates with Type 2 Diabetes and higher risk of cancer.

Genome Integrity and Aging:

• Progeroid syndromes are characterized by cellular defects in metabolism, nuclear integrity, and nucleotide repair
• Examining DNA repair mechanisms like P53 and telomere regulation provides insight into aging processes.

P53: The Guardian of the Genome

• p53 regulates cellular senescence, a response to cellular stress, and prevents cancerous growth.
• 50% of human cancers stem from mutations in p53's DNA-binding domain.
• Moderate damage triggers DNA repair; severe damage causes cellular senescence or apoptosis.

Cellular Senescence as a Defence Mechanism

• Cellular senescence is stable cell-cycle arrest, primarily for pre-cancerous cells.
• Telomere loss triggers cellular senescence.
• Other reasons such as nuclear integrity and DNA damage can trigger cellular senescence.

Telomeres

• Telomeres are repetitive DNA sequences at chromosome ends, acting as protective caps.
• DNA polymerase can't reach the end, so telomeres shorten with each replication cycle.
• This shortening contributes to cellular and organismal aging.

Hayflick Limit

• The Hayflick limit is a finite number of cell divisions in cell culture.
• The number of divisions depends on the organism's life expectancy.
• Loss of telomeres correlates with the Hayflick limit.

DNA Synthesis

• DNA polymerase can only carry out synthesis in a 5' to 3' direction.
• RNA primers are needed, followed by elongation and repair, to ensure genome stability and replication.

Chromosome End Problem

• DNA synthesis reaches a limit due to RNA primer-based DNA replication.
• The 5' end of a chromosome cannot be completely duplicated.
• This leads to shortening of telomeres.

Telomerase

• Telomerase is an enzyme that adds repetitive DNA sequences to telomeres.
• This elongation compensates for shortening during DNA replication.
• Telomerase is found in germline and embryonic stem cells, but usually reduced in adult cells.
• Cancer cells often have upregulated telomerase.

Telomerase and Aging

• Telomere loss can lead to reduced cell replication, increased cellular senescence and potentially to the accumulation of senescent cells in the organism.

• Aging is a complex process driven by a range of factors, including telomere shortening, and incomplete DNA replication, cellular senescence and stress response mechanisms.