What are the 3 major views/groups of why we age?
- Wear and tear
- Adaptive evolutionary
- Non-adaptive evolutionary
What is the wear and tear theory and why can it not be the whole answer?
- View organism as a machine that wears out
- Some organisms wear out (eg. teeth), contributing to deleterious ageing
- BUT some organisms can repair whole organs and not age
- Therefore wear and tear cannot be the whole answer as if body has potential to repair itself, why don't we?
Describe the adaptive evolutionary theory and its problems
- Developed through process of evolution + natural selection
- Conforms to popular Darwinian principles
- Ageing selectively advantageous to species
- Prevents old + worn out individuals competing
- BUT.. advantage to population not individual
- Ageing rarely seen in natural populations
- Prevents old + worn out individuals competing
What are the 2 theories that underly non-adaptive evolutionary reasons for why we age?
- Mutation Accumulation
- Antagonistic pleiotropic genes
What is meant by the mutation accumulation theory?
- Powers of natural selection decline w/ age
- Early expressed genes affect most of population
- Those expressed after reproduction are lost from evolutionary control
- Ageing due to a miscallaneous collection of late acting deleterious genes
- No experimental support for this theory
What is meant by the 'antagonistic pleiotropic genes' theory?
- Genes have more than one effect
- Early good effect therefore retained
- Bad/deleterious late effect which contributes to ageing
- Evidence in drosophila studies
Describe examples of evidence for the theory of antagonistic pleiotropic genes
- Drosophila studies - 2 examples
- aa allele greatly increases early fecundity (fertility) and pleiotropically reduces longevity
- if breeding prevented until later in life over 15 generations lifespan extended by 1/3 but short-winged + flying ability reduced
What is the disposable soma theory?
- development of non-adaptive evolutionary views
- theory views organism as machine that transfers free energy -> progeny
- success is to ensure survival of genes in most efficient way
- disposable = prod with limited lifespan
- soma = not of germ line
- 'your body is dispoable but you have to hand your germ line on'
Disposable Soma theory: Which process will any organism give most attention to and why?
- The amount of energy expended on various possibilities will depend on the ecological niche occupied by that organism (eg. cat, mouse from lecture notes)
- This will result in species specific longevity
- For some fertility is priority
- Others need to maintain soma for longer
What does the second law of thermodynamics suggest?
- Entropy increases ie. we age + decay
- We resist this with defensive + repair processes
- Protective mechanisms eventually fail
- Rate of ageing is determined by investment in self maintenance
- We are programmed to survive not age
How do we age - what are the four groups of theories?
- System level theories
- Cellular/molecular level theories
- Genetic theories
- Genomic stability
A theory based on total body systems is the Neuroendocrine theory. What is it?
- Suggests functional decrease in neurones + associated hormones is central to ageing process
- HPA axis controls growth + dvpt so why not ageing?..
What is the evidence for the neuroendocrine theory?
- Decreased pulsatile GH and GnRH release in ageing rats
- Hypophysectomy + hormone replacement -> inc lifespan
- DECO or death hormone proposed but never found
Cellular theories: Wear and tear + rate of living - what is it?
- Some aspects of ageing look like wear + tear
- Organisms w higher basal metabolic rate have shorter lifespan
- Accumulation of damage may be important
Cellular theories: Cross link formation - what is it?
- Many biological molecules develop cross linkage or bonds w passage or time, altering physical/chemical properties
- Collage is able to cross link - leading to changes in skin, younger person has stretchier/resistant skin compared to old person.
Cellular theories: Heat shock proteins - what is it?
- Heat shock proteins produced at time of cell stress
- Disassemble damaged proteins + transport in new
- Reduced production w/ age
- Decreased ability to cope w stress leads to ageing
Cellular theories: Hayflick phenomena - what is it?
- Fibroblasts grown in culture undergo a set number of divisions then stop
- More divisions if from younger source
- Repeated in other cell types
- Biological clock
- HeLa cell line from Ca breast unlimited divison
The genetic theory can explain for how ageing occurs. What observations/experiments suggest genes are important in this?
- Twin studies
- Long lived families
- Species specific longevity
In which 3 organisms were genes identified that shorten and lengthen life?
Drosophila, yeast, nematodes
In nematodes, there's a mutation that doubles 3/52 lifespan by increasing superoxide dismutase
What are telomeres and what is their purpose?
- Chromosome tail, repeated short DNA base sequence
- Stabilise chromosome during cell division
- Shorten with each division
How are telomeres relevant to explaining ageing?
- Telomeres reach a critical length at which no further divisions can occur -> shorter -> ageing
- Explain Hayflick phenomena (cellular theory) but more importantly telomere length regulates gene (ISG15) expression in human cells
- In germ cells + tumour cells, telomerase is made, which re-expands the telomere and allows for continued cell divison
Genomic stability can account for how ageing occurs. What is error catastrophe?
Errors occur at transcription and translation that result in abnormal protein production, it's usually corrected when protein is replaced
- If the abnormal protein is important in DNA repair/protein synthesis -> may lead to a cascade + cell death
- Accumulation of such errors may result in ageing
Genomic stability: What is meant by somatic mutation and DNA repair?
- Based on irradiation shortening the life span of mice so perhaps ageing due to background radiation causing damage to DNA?
Why is somatic mutation now considered unimportant in relation to ageing?
- Occurence rate is too low
- DNA repair sufficient enough
Despite the unimportance of somatic mutation, repair may fail in combination with toxic agents eg. UV light or O2 radicals. What evidence is there for this?
- DNA repair more efficient in man than in mouse
- Also more efficient in germ cells
- Ability to repair declines w/ ageing (more cancer cells seen)
Genomic stability: What is the free radical theory?
- Highly reactive chemical compounds arise from enzymatic and non-enzymatic reactions
- These damage cellular DNA
- Several enzymes (superoxide dismutase, catalase, glutathione peroxidase) & vit E, C, carotene protect cells/prevent damage
- Protection reduces with age
Genomic stability: What is the mitochondrial theory?
- Ageing due to mitochondrial DNA damage
- High exposure to O2 radicals
- No protein coat to mitochondrial DNA (less protected than nuclear DNA)
- Damage and mutation increase with age
- Genetic mitochondrial dysfunction syndromes mimic ageing
What is cell senescence?
Cellular senescence is the phenomenon by which normal diploid cells cease to divide. In culture, fibroblasts can reach a maximum of 50 cell divisions before becoming senescent. This phenomenon is known as "replicative senescence", or the Hayflick limit. It's basically ageing.
What factors can act on a pre-senescent cell to make it enter into its senescent phase?
- Dysfunctional telomeres
- DNA damage
- Oxidative stress
- Strong mitogenic signals
- Chromatin perturbations
What 3 main things occur within the senescent phenotypic cell?