1b// Biology of Aging Flashcards
What are some definitions of aging?
a progressive accumulation of changes in the body which occur with the passing of time and which cause the increase in the probability of disease and death of the individual.
the wearing out of the structures and functions that reach a peak or plateau during development and maturations of the individuals of a given species.
the time-related deterioration of the physiological functions necessary for survival and reproduction
What is longevity?
defined as the length of the lifespan independent of aging. This makes sense, as two individuals with similar lifespans are unlikely to ‘age’ at the same rate.
What is the difference between aging and longevity?
Longevity may have evolved to maximise opportunities to reproduce (i.e. to maximise ‘reproductive fitness’ in evolutionary terms), whereas aging may be a more random process arising from the impact of events over the life-course.
What has the first research about aging in the 1890s suggests about aging?
Weissmann suggesting that aging had evolved to benefit species by removing older members of the population to reduce competition for resources between younger members of a species, thus improving their reproductive fitness.
What are the 2 major groups of aging theories?
the damage theories of aging and the program theories of aging
Describe the damage theories.
Organisms experience environmental assaults throughout their lifespan. These insults can arise from external impacts (eg UV exposure), or from intrinsic physiological processes (eg Reactive Oxygen Species (ROS) generated from biochemical processes.
Damage (or error) theories of aging postulate that the cumulative impact of these assaults over the lifecourse causes aging.
While the damage theories of aging is generally widely accepted, the precise nature of the damage that causes aging, and how this manifests as aging, remains unclear.
Give the name of 5 theories within damage theories of aging.
wear and tear theory
rate of living theory
cross linking theory
free radical theory
somatic DNA damage theory
What is the wear and tear theory?
Wear and tear theory – over time the components of cells and tissues eventually wear out, leading to the aging of the organism.
What is the rate of living theory?
Rate of living theory – an organisms rate of basal metabolism determines its lifespan - the higher the basal metabolism, the shorter the lifespan (eg rodents vs humans)
What is the cross-linking theory?
Cross-linking theory – accumulation of cross-linked proteins over time impairs cellular function, slowing down bodily processes and leading to aging
What is the free-radical theory?
Free-Radical Theory – reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function. Accumulation of this damage over time results in aging.
What is the somatic DNA damage theory?
Somatic DNA damage theory – genetics mutations are acquired faster than they can be repaired. These accumulate over time leading to a breakdown of genetic integrity, resulting in aging.
Describe the programme theories.
Program theories of aging suggest that aging follows a biological timetable. This programme might be a continuation of the growth and development programmes of fetal life and childhood.
Certainly there are some single-gene mutation disorders (such as Hutchinson-Gilford Progeria syndrome) which have many characteristics of accelerated or pre-mature aging, and suggest that aging might be pre-programmed genetically.
Program theories of aging are less widely accepted, and less well supported by evidence.
In reality, it is likely that there is no single thing which drives biological aging, but instead a combination of accumulating damage and (epi?)genetic dysregulation may underpin biological aging.
Give the name of the 3 programme theory theories.
programmed longevity
endocrine theory
immunological theory
What is programmed longevity?
Programmed longevity – this suggests that aging arises due to time-dependent changes in expression of key genes involved in growth or development.
What is endocrine theory?
Endocrine theory – this suggests that hormonal influences (eg GH-IGFI signalling) constitutes a biological clock that determines the rate of aging of an organism
Explain genomic instability.
DNA damage is accumulated throughout life from exposure to external sources (eg UV radiation) or body processes (eg free radicals). Some premature aging syndromes (Werner, Blooms) arise from mutations in DNA repair enzymes – indicating a link between aging and genetic integrity.
Within nuclear DNA, changes in copy number and chromosome stability are observed with increasing age, but there are also changes to nuclear architecture (how the DNA is arranged and packaged within the nucleus) and to the mitochondrial DNA. Failure to remedy these changes leads to cellular dysfunction, which accumulates, leading to aging.
Explain epigenetic changes.
Aging is associated with distinct epigenetic changes, including loss of DNA methylation, age-specific patterns of histone modification, and changes in the expression of enzymes that regulate DNA packaging and chromatin remodelling. Together, these lead to inappropriate expression of genes (transcriptional noise) and changes in the packaging and accessibility of DNA to proteins, which in turn can lead to impaired DNA repair and chromosome instability.
Explain telomere attrition.
The ends of chromosomes contain repeated DNA sequences known as telomeres. In most cells, telomeres cannot be replicated fully by the DNA replication machinery, so shorten with each round of cell division, and once the telomere reaches a critical shortness, cells enter senescence (stop dividing). Some cells (mostly stem cells) express an enzyme called telomerase, which can maintain telomere length, and experimental manipulation of telomere length or telomerase expression can modulate mammalian lifespan.
Progressive loss of telomeres over the lifecourse of the organism is thought to lead to cellular senescence and an inability to maintain homeostasis in tissues, resulting in aging.
What is stem cell exhaustion?
Decline in the regenerative potential of tissues is a key hallmark of aging. Cell cycle activity in aged stem cells is reduced, leading them divide less frequently, and thus contribute less to repair and maintenance of tissues, resulting in aging. The stem cells may also accumulate mutations, leading to the formation of neoplasias.
The diagram below shows how changes in Haematopoietic Stem Cells (HSCs), Mesenchymal Stem Cells (MSCs), Satellite Cells, and Intestinal Epithelial Stem Cells (IESCs) with age could contribute to organ dysfunction and ageing.
What is cellular senescence?
Senescence is the stable arrest of the cell cycle, and occurs in response to DNA damage, and prevents the ongoing proliferation of these dysfunctional cells. These cells are efficiently removed by the immune system, preventing progression to cancer or aging, with removed cells are replaced by stem cell activity.
In aged cells, senescence still occurs, but stem cell activity is less efficient, so removed cells do not get replaced as effectively, thus the demand for replacement cells may increase, thus exhausting the capacity of the stem cells. Senescent cells also secrete pro-inflammatory cytokines, which may contribute to aging.
What is impaired proteostasis?
Proteostasis controls the normal folding and maintenance of proteins in their folded state through chaperone (heat shock protein) activity). Normally, unfolded proteins are targeted for autophagy, or breakdown by the proteosome. However, persistence of unfolded proteins leads to their aggregation, disrupting normal cell function, a situation associated with numerous age-related disorders (eg Alzheimers, Parkinsons).
Can we treat biological aging?
Identifying the hallmarks of aging provides targets for anti-aging research. If the hallmarks of aging are causative, then developing therapeutics that target one or multiple hallmarks may help slow the aging process/increase longevity.
Strategies to address each of the hallmarks are summarised in the figure below:
Many of the ideas in the figure above are being actively pursued by research teams around the world, but increasingly there has been a great deal of private sector interest (and start-ups forming) to pursue therapies based around these approaches.
Do you understand all these points?
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