“The hallmarks of ageing”

By Pia Skok

Ageing is defined as a functional decline and deterioration in organism’s lifetime.1 We often associate ageing with decrease in cognitive function, mobility issues and less elastic, more fragile skin. But what are the biochemical reasons behind these commonly observed ageing symptoms? There are nine molecular and cellular hallmarks of ageing that together contribute to the ageing process and give rise to the ageing phenotypes: genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, senescence, loss of stem cell, and altered intercellular communication.1

            The first hallmark to be implicated in ageing was genomic instability, likely because of its prominent role in many age-related diseases such as cancer.  Our genome is constantly exposed to exogenous physical, and chemical agents, which cause chemical damage (i.e. strand breaks) and mutations leading to genomic instability.2 Most of these changes are repaired by various DNA repair pathways, however, over time and with a decline in DNA repair mechanisms, DNA lesions accumulate. This can lead to alterations in gene expression and give rise to dysfunctional cells that affect tissue homeostasis and give rise to the ageing phenotype.1

In addition to alterations in the genome nucleotide sequence, ageing is also caused by epigenetic changes including alteration to DNA methylation patterns, post-translational modifications of histones and chromatin remodelling. It has yet to be determined whether these changes lead to aging via by causing altered transcription of genes encoding key components of inflammatory, mitochondrial, and lysosomal degradation pathways or by affecting DNA repair and genome stability.1

Another ageing hallmark closely associated with genomic instability is telomere shortening. Telomeres, which protect genome from degradation, shorten every cell division. Therefore, as we age telomeres become progressively shorter until they reach a critical length that induces cell senescence and/or apoptosis. Studies have shown that specific lifestyle factors such as diet and exercise affect the rate of telomere shortening and can affect the onset of ageing and age-related diseases.3

For the cell to function properly it must maintain a stable and functional proteome. This is achieved through coordinated function of protein folding by molecular chaperones and protein degradation by proteasome or lysosome. Studies have shown that as we age cells lose the ability to maintain proteostasis due to the dysfunction of mentioned quality control mechanisms. As a result, abnormal proteins accumulate in the cell in the form of aggregates and occlusions which are toxic and interfere with cellular processes such as intracellular transport.4 Additionally, aggregation of specific proteins such as amyloid beta and alpha synuclein gives rise to age-related diseases such as Alzheimer’s and Parkinson’s disease respectively.1

In addition to the proteome, a crucial role in ageing is also played by various metabolic pathways. Evidence suggests that anabolic signalling accelerates ageing while decrease in nutrient sensing slows it down.1 For example, it has been shown that by decreasing the signal intensity in the glucose sensing insulin-like growth factor (IGF-1) and insulin pathway extends the lifespan of mice. This suggests that deregulation of nutrient sensing which can be achieved through dietary restriction has the potential to extend longevity.5

            Another important hallmark of ageing is mitochondrial disfunction although the exact details of how mitochondrial disfunction contributes to aging remain to be determined.1 As organisms age, the mitochondria become less efficient causing electron leakage and lower ATP production during cellular respiration. This results in oxygen reactive species which can cause global cell damage as well as trigger the permeabilization of mitochondrial membranes resulting in apoptosis.6

            On a cellular level aging is caused by senescence and loss of stem cells. Cellular senescence, which refers to a stable arrest of the cell cycle, can be caused by telomere shortening and/or DNA damage. Accumulation of senescent cells because of their decreased clearance as we age leads to increased inflammation and decrease in tissue function as senescent cells induce senescence in neighbouring cells. Therefore, senescence has a pro-ageing effect.1 In contrast, ageing can also result from exhaustion of stem cells which play a crucial role in tissue maintenance and regeneration due to their ability to differentiate into any cell type. As we age stem cells acquire various defects previously mentioned such as epigenetic changes, DNA damage and loss of healthy proteome which impair their function leading to an ageing phenotype.7

Lastly, ageing is characterised by defects in intercellular communication. As organism ages, an increase in inflammation and changes in extracellular environment are observed which affect neurohormonal signalling. Consequently, the mechanical and functional properties of tissues are compromised causing age-related phenotypes such as muscle weakness and reduced neurogenesis.1

 Ageing is a complex phenomenon that is not caused by a single factor but instead a combination of molecular and cellular reasons commonly known as hallmarks of ageing. Because these hallmarks are highly intertwined ageing research is extremely challenging and there are still many problems to address before we have a complete understanding of this complex biological process. However, once the hallmarks and their exact mechanism of how they cause ageing is understood in detail there is a potential to prolong both human health- and lifespan.  

References:

  1. Lopez-Otin, C. et al. (2013) The Hallmarks of Ageing. Cell. 153(6):1194-1217. doi: https://doi.org/10.1016/j.cell.2013.05.039

2. Vijg, J. and Suh, Y. (2013) Genome Instability and Ageing. Annual Review of Physiology. 75: 645-668. doi: https://doi.org/10.1146/annurev-physiol-030212-183715

3. Shammas, M. A. (2011) Telomeres, lifestyle, Cancer and Aging. Curr Opin Clin Nutr Metab Care.  14(1): 28-34. doi: 10.1097/MCO.0b013e32834121b1

4. Koga, H. et al. (2010) Protein homeostasis and aging: The importance of exquisite quality control. Ageing Res Rev. 10(2):205-15. doi: 10.1016/j.arr.2010.02.001.

5. Fontana, L. et al. (2010) Extending healthy life span–from yeast to humans. Science. 328(5976):321-6. doi: 10.1126/science.1172539.

6. Green, D. R. (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 333(6046):1109-12. doi: 10.1126/science.1201940.

7. Ermolaeva, M. et al. (2018) Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol. 19, 594–610. doi: https://doi.org/10.1038/s41580-018-0020-3

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