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Sex, Life, Death & Theories of Ageing, Disposable Soma Theory - Coggle…
Sex, Life, Death & Theories of Ageing
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Ageing and Reproduction
Effects of Reproduction
- Restricting reproduction late age in Drosophila increased longevity (Zwann et al., 1995)
- Sexual differentiation induces ageing-like change. Asexual animals maintain telomere length through regeneration (Tan et al., 2012), sexual animals appear to only lengthen telomeres through sexual reproduction process.
- 271 bird species, strong relationship between relative longevity and age at first reproduction. Positive relationship. Older reproduction = longevity more (Møller, 2006)
- longevity linked to small number offspring among female members British aristocracy (Doblhammer, 2003)
- 20000 women, odds longevity significantly higher women with later age at first childbirth (Shadyab et al., 2017)
- Appears genetically controlled
Menopause
- Reproductive senescence age 45-50, unique in humans but orcas also have it
- In pre-history, humans may not have lived much beyond this, so menopause reflects normal lifespan
- Menopause may evolved to prevent giving birth at older age (when more likely die childbirth) ensuring mother survives long enough to raise offspring (mother hypothesis)
- May allow grandmothers to increase fitness by helping with rearing grandchildren at age when too frail to have children of own (grandmother hypothesis)
- BUT not mutually exclusive and difficult to test
Programmed Ageing ageing controlled by genes
- Disorders may show the process of ageing, e.g., it may be related to faulty DNA repair
Ageing Disorders
Werner Syndrome
- rare, inherited disorder. Rapid ageing (National Cancer Institute, 2011)
Adult progeria (progeroid syndromes involve mutations genes involved DNA repair and transcription)
- Onset adolescence, longevity m=47, involves many ageing symptoms and increased cancer rate National Cancer Institute, 2011)
- Caused by mutation WRN gene, coding for type of RecQ DNA helicase, protein involved in DNA replication
- WRN could be involved in disrupting DNA structures formed by illegitimate interactions between DNA strands during DNA replication, repair, transcription and recombination, thus maintaining overall genomic stability. Perhaps goes wrong in non-pathological ageing (Martin & Oshima, 2000)
Hutchinson-Gilford Progeroid Syndrome
- Genetic condition with striking features resembling premature ageing. (National Organization for Rare Disorders, 2015)
- Onset childhood, longevity m=13, ageing-like symptoms like strokes at 9 years old
- Caused by mutation lamin A gene (LMNA) codes for protein that forms filaments inside cell nucleus and can bind to DNA. Mutation causes deformed nucleus, associated with genomic instability. In normal ageing, it redistributes away from sites in nuclear interior, associated with decline in nuclear morphology and increased evidence DNA damage (Kudlow & Kennedey, 2006)
Cellular Senescence
- Biochemical stress can induce cell senescence, causing replicative senescence
- such stress includes DNA damage, chromosomal proteins and expression of oncogenes (cancer-related genes; Micco et al., 2021)
- Evidence that senescent cells accumulate with age in tissue e.g., mice ageing consistent age-dependent increases in expression of molecular hallmarks senescence in most tissues (Hudgins et al., 2018)
- Link between ageing and stem cell depletion (Mi et al., 2022). Stem cells have tissue repair capabilities and essential for maintaining tissue homeostasis
Replicative Senescence and Telomeres
- Telomeres 'cap-like' regions end of each chromosome that protect genetic info near end of chromosome (Shammas, 2011), like plastic on end of shoelace. They shorten with each replication
- When DNA replicates, small amount DNA not replicated when chromosome divides, causing telomeres to get smaller and smaller until cell division stops Thus shortens with age (Shammas, 2011)
- Telomerase enzyme restores telomere length and has been shown to reverse many effects cellular senescence (Rossiello et al., 2022) expression telomerase led to Telomere-associated DDR foci (marker cellular senescence) reduction, decreased inflammation and improved lung function in telomerase-mutant and wild-type mice.
- BUT telomerase deficient mice do not age faster, so telomeres cannot regulate ageing at organism level
- Most cancer cells overexpress telomerase to become immortal, hence telomere shortening and cellular senescence may be adaption to protect against cancer. Perhaps trade-off between lengthening cellular lifespan and preventing cancer (Mathon & Lloyd, 2001)
- This premature, replicative senescence and consequential telomere shortening could contribute to progressive bodily function associated with ageing
Apoptosis
- Tightly genetic-control programmed cell death can occur in response internal or external signals, and is part of normal development and cellular turnover
- Implicated in cancer - apoptosis can be initiated by tumour suppression protein p53 (Ozaki & Nakagawara, 2011), and deficiency p53 strongly increases cancer rates in mice BUT equally excess p53 causes tissue damage and physiological effects that look like ageing (Donehower, 2009)
- Mice correlated elevated p53 activity with either early ageing or delayed-onset ageing (Wu & Prives, 2018)
Gene Regulation Theory of Ageing
- Ageing result of changes gene expression. Genes unlikely to promote senescence as such, but rather promote longevity and/or other functions influence lifespan
- Klotho deficiency (transmembrane protein involved in insulin signalling) mice show accelerated ageing symptoms (Kurosu et al., 1997)
- Overexpressing Klotho mice have 30% longer lifespan (Kurosu et al., 2005)
- Longevity in humans strong genetic component (e.g., if mum lived long, then you will). Locus on chromosome 4 linked with longevity, but unclear why (Puca et al., 2001)
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Extending the Lifespan
Caloric Restriction
- Reducing by 40% can increase lifespan animals, but possibly only in captivity
- Biosphere experiment humans, people 30% reduction caloric intake 18 months caused physiological changes similar to in animal models. E.g., in rats (Mattson, 2005) and monkeys (Colman et al., 2008)
- Okinawa greatest proportion centenarians world, low caloric intake less than 40% average US diet
- Increases stress resistance, immune response, changes gene expression, reduces free radicals, may involve shift low-energy metabolism, negative effects growth and sexual maturation
- possible adaptive response food shortage
- reduced fertility and extended lifespan permits delaying reproduction until food becomes abundant
:warning: add to this from lecture 6
Antioxidants
- Vitamin E natural antioxidant food supplement known reduce oxidative damage, however animal studies not clearly shown any effect vit E lifespan.
- Only compelling data C elegan worms compound EUK-134 lifespan extension
:warning: check lecture 6
Parabiosis
- surgically connecting 2 animals so share same bloodstream. (Ashapkin et al., 2020)
- Old parabionts show ageing reversal signs when connected to young individual. Improvements cognitive function, synaptic plasticity and stem cell activity.
- Limited evidence, blood transfusion elderly can temporarily halt ageing process
Oxytocin
- hormone controlling lactation, birth, maternal/paternal behaviours.
- Levels decline with age (Benameur et al., 2021)
- Inhibition oxytocin signalling young animals reduces muscle regeneration, whereas Administering oxytocin to old animals helps muscle regeneration by enhancing aged muscle stem cell activation/proliferation.(Elabd et al., 2015)
- genetic lack oxytocin does not cause developmental defect in muscle, but leads to premature sarcopenia (gradual loss muscle mass, strength and function commonly affects elderly)
- Yim et al. (2016) oxytocin linked to oxytocin receptor to telomere length
Rapamycin
- drug used treat cancer and suppress immune system function patients organ transplants
- Extends lifespan in mice, but likely due to anti-tumour effect and raised risk diabetes (Wilkinson et al., 2012)
IN SUMMARY
- Ageing complex process involving many factors representing failure to maintain/repair body indefinitely (Stochastic ageing)
- Unclear how ageing genes could evolved
- Several lines evidence suggest rate ageing subject genetic control, perhaps adaption large variability environmental conditions
- Programmed ageing remains controversial, stochastic well explained by evolutionary theory
Disposable Soma Theory
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Summary
- Animals rarely/never age in wild, only small number survive into old age to have impact natural selection.
- Ageing has not evolved as adaption, rather immortality has failed to evolve as ageing is a natural consequence of failure to repair/maintain body
- Lifespan varies drastically across species, suggesting effectiveness of repair/maintenance mechanisms is under genetic control
Animals finite amount energy. Either have lots offspring when young, or save it until later to stay healthy for longer and prolong the lifespan. (Kirkwood, 1977)
- As most die young, allocating resources to benefit early survival/reproduction will have higher fitness, even though results in reduced maximum lifespan
- Evidence Resources - white footed mouse lives 2x longer than house mouse and has more cellular antioxidants and lower levels reactive oxygen species (ROS; free radicals). Hyun et al. (2008) in C elegan worms, DNA repair capacity higher in long-lived C elegan mutant than wild. Relationship between longevity and rate ROS production. DNA repair capacity correlates with longevity in mammals, and cells from long-lived species more resistant to stress.
- Evidence fertility - delaying reproduction in pacific salmon maintains body and they live longer, same for Drosophila flies and C. elegan worms (Gems et al., 2021)