Cancer is a problem that affects organisms with renewable tissues; these have evolved tumour-suppressor mechanisms to suppress the development of cancer.
Tumour-suppressor genes act to prevent or repair genomic damage (caretakers), or inhibit the propagation of potential cancer cells (gatekeepers) by permanently arresting their growth (cellular senescence) or inducing cell death (apoptosis).
Some caretaker tumour suppressors seem to postpone the development of ageing phenotypes, and so are also longevity-assurance genes.
The gatekeeper tumour-suppressor mechanisms (apoptosis and cellular senescence), by contrast, might promote certain ageing phenotypes.
Apoptosis and cellular senescence are controlled by the p53 and RB tumour-suppressor pathways, components of which are evolutionarily conserved among multicellular organisms.
The evolutionary hypothesis of antagonistic pleiotropy predicts that some processes that benefit young organisms (by suppressing cancer, for example) can have detrimental effects later in life and would therefore contribute to ageing.
Both apoptosis and cellular senescence might be antagonistically pleiotropic, promoting ageing by exhausting progenitor or stem cells. Additionally, senescent cells secrete factors that can disrupt tissue integrity and function, and even promote the progression of late-life cancers.
Recent studies on p53 provide a molecular basis for how tumour suppression and ageing might be intertwined.
Organisms with renewable tissues use a network of genetic pathways and cellular responses to prevent cancer. The main mammalian tumour-suppressor pathways evolved from ancient mechanisms that, in simple post-mitotic organisms, act predominantly to regulate embryogenesis or to protect the germline. The shift from developmental and/or germline maintenance in simple organisms to somatic maintenance in complex organisms might have evolved at a cost. Recent evidence indicates that some mammalian tumour-suppressor mechanisms contribute to ageing. How might this have happened, and what are its implications for our ability to control cancer and ageing?
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Saccharomyces Genome Database
- COMPLEX ORGANISMS
Multicellular organisms that are composed of both post-mitotic and renewable (mitotic) somatic tissues.
- SIMPLE ORGANISMS
Multicellular organisms that are composed entirely or largely of post-mitotic somatic cells.
Tumour-suppressor genes or proteins that act to protect the genome from damage or mutations. Many caretaker genes encode proteins that recognize or repair DNA damage.
Tumour-suppressor genes or proteins that regulate cellular responses that prevent the survival or proliferation of potential cancer cells. These responses are known as apoptosis and cellular senescence, respectively.
- NUCLEOTIDE EXCISION REPAIR
A DNA-repair pathway that removes and replaces damaged nucleotides, particularly those that distort the DNA helix.
The DNA–protein structure that stabilizes the ends of linear chromosomes and protects them from degradation or fusion. In vertebrates, telomeres are composed of several-kilobase pairs of the sequence TTTAGGG and several associated proteins.
Ordered, genetically programmed cell death triggered by both physiological stimuli and cellular damage. Apoptosis avoids cell lysis and subsequent inflammation.
- CELLULAR SENESCENCE
The essentially irreversible loss of cell division potential and the associated functional changes that are triggered by damage and other potential cancer-causing stimuli.
Average or maximum lifespan of a cohort of organisms.
The decline in organismal fitness that occurs with increasing age.
- AGEING PHENOTYPES
The specific physiological manifestations of ageing.
- ANTAGONISTIC PLEIOTROPY
The hypothesis that genes or processes that were selected to benefit the health and fitness of young organisms can have unselected deleterious effects that are manifest in older organisms and thereby contribute to ageing.
- MISMATCH REPAIR
A DNA-repair pathway that removes and replaces nucleotides that have been misrepaired by DNA polymerases during DNA replication.
- BASE EXCISION REPAIR
A DNA-repair pathway that excises and replaces damaged DNA bases.
- NON-HOMOLOGOUS END-JOINING REPAIR
A relatively error-prone pathway that repairs double-strand breaks by ligating non-homologous DNA ends.
- HOMOLOGOUS RECOMBINATIONAL REPAIR
A relatively error-free pathway that repairs DNA double-strand breaks using an undamaged sister chromatid or homologous chromosome as a template.
- XERODERMA PIGMENTOSUM
A group of cancer-prone syndromes in humans that are caused by defects in the nucleotide excision repair genes.
Passive or unregulated cell death, in which cells lyse and deposit degradative and antigenic cell constituents into the surrounding tissue. Necrotic cell death, in contrast to apoptosis, often provokes an inflammation reaction.
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