Why do we age? What factors influence our lifespan?
Physiological aging
Respiratory Function: lungs show impaired gas exchange, a decrease in vital capacity and slower expiratory flow rates
Cardiovascular: cardiac output decreases, blood pressure increases
Musculoskeletal: reduction in the size, elasticity and strength of all muscle tissue, smaller muscle fibers, decrease in reserves of ATP & glycogen, Osteoporosis: linear decline in bone mass
Endocrine & Metabolism: reduction in hormone production, diabetes, elevation of blood glucose
Skin: loses collagen & elastin, dermis decreases in thickness by about 20%, fragile, slow to heal, Sensory neurons are decreased by 30%
Neurosensory: loss of neurons, sense of smell, taste, sight, touch and hearing are all diminished
risk factor for: cancer, heart disease, neurodegenerative conditions, osteoporosis, arthritis, diabetes
programmed cell death (apoptosis)
multiple morbidities
Factors affecting trajectories of ageing
accumulation of defects that stem from random damage
influenced by genetics, environment and behaviour
ageing is malleable
lower socio‐economic status --> shorter life expectancy
nutrition, smoking, lifestyle, physical activity, environment, attitude
heritability ca. 25%
Mediterranean diet
Hormesis: moderate exposure to a damage‐inducing agent confers an overall benefit by stimulating upregulation of maintenance eg. exercise
Dietary restriction: improves metabolic health, prevents obesity
meal timing: intermittent fasting
Protein restriction
selective amino acid restrictions
DNA repair, mitochondrial function, insulin sensitivity, stem cell function, tissue repair, improved organ function, resistance to stress
increased production of the neurotrophic factors BDNF
reduced inflammation & oxidative stress
effects of diet on health may be age specific
nutrition in early life (including in utero) can have lasting effects on health during aging
Females and males often respond very differently to dietary and pharmacological interventions
Molecular Mechanisms
Mitochondrial Theory
Altered Proteins Theory and Waste Accumulation Theory
Telomere Loss Theory
Network Theories
Somatic Mutation Theory
age-related increases in somatic mutation and other forms of DNA damage
capacity for DNA repair as determinant of the rate of aging
relationship between longevity and DNA repair
Higher enzyme PARP-1 activity levels associated with longer life spans
decline in cellular division capacity with age
telomeres protect the ends of chromosomes & get progressively shorter as cells divide
absence of the enzyme telomerase
suggested that in dividing somatic cells, telomeres act to protect us against runaway cell division eg. cancer but causing aging as the price for this protection
stress has effect on telomere loss
accumulation of mitochondrial DNA (mtDNA) mutations with age
mtDNA mutation --> impaired ATP production --> decline in tissue bioenergenesis.
impairment of protein turnover
accumulation of altered proteins
contributions of the various mechanisms are considered together, allowing for interaction
differences between “upstream” and “end stage” mechanisms
Evolutionary theories (provide complementary explanations)
senescence is programmed in order to limit population size or accelerate the turnover of generations, thereby aiding the adaptation of organisms to changing environments--> wrong because there is little evidence that senescence contributes to mortality in the wild
Mutation-accumulation theory
Pleiotropy theory
Disposable soma theory
random mutations causing adverse aging characteristics
genetic diseases, which have adverse symptoms only at advanced ages
Selection shadow:
selection pressures on an individual decrease as an individual ages and passes sexual maturity, resulting in a "shadow" of time where selective fitness is not considered, also allows alleles with late deleterious effects to accumulate over the generations with little or no check
one gene influences two or more phenotypic traits
genes with good early effects would be favoured by selection even if these genes had bad effects at later ages --> trade off
optimal allocation of metabolic resources between somatic maintenance and reproduction
Extrinsic mortality: result of environmental hazards, is constant over age
Testing the theories
applying artificial selection on life-history variables or by intra- and interspecies comparisons of populations that are subject to different levels of extrinsic mortality
selection experiments using fruitflies: By restricting reproduction to later ages, the intensity of selection on the later portions of the life span was increased--> supports disposable soma & pleiotropy theories
evidence for the mutation-accumulation theory remains more controversial (should be revealed by an increase in additive genetic variance in mortality rate at later ages.)
DNA repair capacity has been shown to correlate with mammalian life span (evidence for disposable soma theory)
laboratory rodents under caloric restriction show enhanced resistance to a range of stresses
similarities between the caloric-restriction state and that of mammalian hibernation
Reproduction
semelparity: single reproductive episode before death, death after reproduction, force of natural selection approximates a step function
iteroparity: multiple reproductive cycles throughout the lifespan (humans)
Whether or not there is significant post-reproductive survival may be governed chiefly by whether or not the post-reproductive adult contributes actively to the survival chances of the offspring.
Human menopause:
- fitness advantage in limiting reproduction to ages when it is safe, thereby increasing the likelihood of the mother surviving to raise her existing offspring to independence.
- post-menopausal women may contribute to the successful rearing of their grandchildren, by providing assistance to their own adult offspring and thereby increasing their inclusive fitness, --> overall genetic contribution to future generations
The evolutionary theories of ageing predict:
- Specific genes selected to promote ageing are unlikely to exist
- Ageing is not programmed but results largely from accumulation of somatic damage, owing to limited investments in maintenance and repair. Longevity is thus regulated by genes controlling levels of activities such as DNA repair and antioxidant defence.
- There may be adverse gene actions at older ages arising either from purely deleterious genes that escape the force of natural selection or from pleiotropic genes that trade benefit at an early age against harm at older ages.