S377 Chapter 18

Most types of molecule and cellular component of animal cells are affected during [blank_start]ageing[blank_end], and different types of animal cells have [blank_start]different lifespans[blank_end].

Cellular ageing is studied using cells from model organisms that have very different lifespans.

Two of the many theories of ageing are the n[blank_start]etwork theory[blank_end], which states that cellular ageing is the result of a [blank_start]combination of processes[blank_end], and the f[blank_start]ree radical theory[blank_end], according to which [blank_start]free radical damage[blank_end] is the cause of [blank_start]molecular and cellular ageing[blank_end].

Genes that confer protection against [blank_start]free radicals[blank_end] and other stresses may have a positive effect against molecular and cellular damage occurring during [blank_start]ageing[blank_end], but will only be selected for by evolution if they also promote [blank_start]reproductory fitness[blank_end].

Vertebrate tissues have a mixture of [blank_start]post-mitotic[blank_end] non-dividing cells, such as [blank_start]neurons[blank_end] and skeletal muscle cells, and [blank_start]dividing[blank_end] cells, such as [blank_start]epithelial cells[blank_end] (and germ cells).

Label the diagram of formation of Reactive Oxygen Species during oxidative phosphorylation at the mitochondria

Free [blank_start]radicals[blank_end] are atoms or molecules that possess [blank_start]unpaired[blank_end] electrons and are therefore very [blank_start]reactive[blank_end].

There are many naturally occurring [blank_start]free radicals[blank_end]; one major source within cells is [blank_start]oxidative phosphorylation[blank_end], which takes place in the inner [blank_start]mitochondrial[blank_end] membrane.

Free radicals cause [blank_start]oxidative[blank_end] damage to all types of molecules and cell organelles. Particularly: DNA damage - [blank_start]double strand breaks[blank_end] and altered bases/nucleosides, chain reactions of free radical formation in [blank_start]lipid peroxidation[blank_end], damage to amino acids causing changes to [blank_start]activity/conformation[blank_end] of the protein.

Cellular defences against free radicals have evolved; these are either primary or secondary defences. Primary defences include small-molecule radical [blank_start]scavengers[blank_end], proteins that bind [blank_start]metal ions[blank_end], and [blank_start]antioxidant enzymes[blank_end]. Secondary defences include [blank_start]repair enzymes[blank_end], [blank_start]stress response[blank_end] proteins and [blank_start]protein degradation[blank_end] systems.

[blank_start]Replicative senescence[blank_end] is the irreversible state reached by proliferative cells when they withdraw from the [blank_start]cell cycle[blank_end], and do not undergo any further divisions. It has been studied by measuring [blank_start]population doublings[blank_end] of cells in culture.

Senescent cells exhibit changes in [blank_start]gene expression[blank_end], which may not only affect their function, but may also affect [blank_start]surrounding cells[blank_end]. They also look different from [blank_start]dividing cells[blank_end], being bigger and having larger nuclei.

Several different events can cause cells to become [blank_start]senescent[blank_end]; these include [blank_start]telomere[blank_end] shortening, some types of DNA [blank_start]damage[blank_end], decondensation of [blank_start]chromatin[blank_end], overactivity of some [blank_start]mitogenic stimuli[blank_end] and activation of some [blank_start]oncogenes[blank_end].

[blank_start]Telomeres[blank_end] may be preferentially susceptible to [blank_start]DNA damage[blank_end], and therefore not only trigger [blank_start]replicative senescence[blank_end] due to [blank_start]shortening[blank_end] caused by repeated cell division, but also act as a type of ‘sensor’ of DNA damaging events, such as [blank_start]oxidative stress[blank_end].

[blank_start]Post-mitotic[blank_end] cells such as [blank_start]neurons[blank_end] and skeletal muscle cells exhibit a number of changes during ageing. These changes include [blank_start]mitochondrial damage[blank_end], abnormalities in [blank_start]protein folding[blank_end], protein [blank_start]accumulation[blank_end], and [blank_start]protein[blank_end] glycation.

[blank_start]Mitochondrial[blank_end] function is impaired with age, and genes encoded by [blank_start]mtDNA[blank_end] are particularly vulnerable to [blank_start]oxidative damage[blank_end].

Changes in protein [blank_start]folding[blank_end] and turnover occur with increasing age. perhaps due to problems with [blank_start]chaperones[blank_end] or the protein [blank_start]degradation[blank_end] system. Accumulation of misfolded or [blank_start]damaged[blank_end] proteins therefore often occurs in long-lived cells such as [blank_start]neurons[blank_end]. These can form insoluble [blank_start]aggregates[blank_end] called [blank_start]amyloid[blank_end] fibrils or plaques, causing [blank_start]disease[blank_end].

Interaction of [blank_start]sugars[blank_end] with amino acid residues starts a series of reactions leading to [blank_start]protein glycation[blank_end] and the accumulation of [blank_start]AGEs[blank_end] (Advanced Glycosylation End-products). Long-lived proteins (e.g. [blank_start]extracellular matrix proteins[blank_end]) are particularly susceptible to damage by [blank_start]glycation[blank_end].

Both mitotic and post-mitotic cells can be affected by genomic instability.

Many segmental [blank_start]progeroid[blank_end] syndromes in humans are due to [blank_start]mutations[blank_end] in genes encoding proteins that play a role in the detection of [blank_start]DNA damage[blank_end], or DNA [blank_start]repair[blank_end]. This suggests that DNA damage plays a role in [blank_start]normal ageing[blank_end].

A [blank_start]mutation[blank_end] in the gene encoding nuclear A-type lamins has also been found in one [blank_start]progeroid[blank_end] syndrome, [blank_start]HGPS[blank_end]. [blank_start]Nuclear lamins[blank_end] are [blank_start]intermediate filaments proteins[blank_end], which form a structural lattice attached to the inner face of the [blank_start]nuclear envelope[blank_end] and play a role in cell [blank_start]division[blank_end] and gene [blank_start]expression[blank_end].

The [blank_start]insulin/IGF-1-like[blank_end] signalling pathway in C. elegans , D. melanogaster and mice affects both [blank_start]stress responses[blank_end] and longevity. Activation of this pathway in these three laboratory model organisms leads to [blank_start]downregulation[blank_end] of stress response genes and [blank_start]reduces[blank_end] lifespan. Although an [blank_start]analogous[blank_end] pathway occurs in humans, and affects [blank_start]growth[blank_end] and metabolism, the effects on stress response genes and [blank_start]longevity[blank_end] are not known.

mtDNA is more vulnerable to oxidative damage because:

[blank_start]mtDNA[blank_end] codes for several [blank_start]proteins[blank_end] that are required in the [blank_start]TCA[blank_end] cycle and the [blank_start]electron transport[blank_end] chain. So if mtDNA is damaged by [blank_start]ROS[blank_end], this has huge repercussions on the cell's ability to [blank_start]generate energy[blank_end]. Combined with other age related damage to [blank_start]mitochondria[blank_end] in [blank_start]post-mitotic[blank_end] cells, to the membrane and proteins, this can be a real problem.