The Genetics of Ageing and Longevity

Ageing is a natural process inherent to all living organisms. Yet, its mechanisms remain somewhat enigmatic. While lifestyle factors undoubtedly influence longevity, recent advancements in genetic research have revealed the influence of our genomes on ageing. Through understanding these influences, we can unlock further knowledge on longevity, which can aid us in developing interventions to promote healthy ageing. This article delves into the world of ageing and longevity genetics and how we can use this understanding to our benefit. 

Longevity genes

A number of longevity genes, such as APOE, FOXO3, and CETP, have been identified. These genes influence various biological processes, including cellular repair, metabolism, and stress response mechanisms. A well-studied longevity gene is SIRT1. Located on chromosome 10, SIRT1 encodes sirtuin 1, a histone deacetylase, transcription factor, and cofactor. Its roles include protecting cells against oxidative stress, regulating glucose and lipid metabolism, and promoting DNA repair and stability via deacetylation. Sirtuins are an evolutionarily conserved mediator of longevity in many organisms. One study looked at mice with knocked-out SIRT1; these mice had significantly lower lifespans when compared with WT mice1. The protective effects of SIRT1 are thought to be due to deacetylating p53, which promotes cell death2. SIRT1 also stimulates the cytoprotective and stress-resistance gene activator FoxO1A (see Figure 1), which upregulates catalase activity to prevent oxidative stress3. Genome-wide association studies (GWAS) have identified several genetic variants associated with ageing and age-related diseases. Such variants influence diverse aspects of ageing, such as cellular senescence, inflammation, and mitochondrial function. For example, certain polymorphisms in APOE are associated with an increased risk of age-related conditions like Alzheimer's and Parkinson’s disease4. These genes have a cumulative effect on the longevity of an organism.

Epigenetics of ageing

Epigenetic modifications, such as histone modifications and chromatin remodelling, regulate gene expression patterns without altering the DNA sequence. Studies have shown that epigenetic alterations accumulate with age and contribute to age-related changes in gene expression and cellular function. For example, DNA methylation is downregulated in human fibroblasts during ageing. Furthermore, ageing correlates with decreased nucleosome occupancy in human fibroblasts, thereby increasing the expression of genes unoccupied by nucleosomes. One specific marker of ageing in metazoans is H3K4me3, indicating the trimethylation of lysine 4 on histone 3; in fact, H3K4me3 demethylation extends lifespan. Similarly, H3K27me3 is also a marker of biological age. By using these markers as an epigenetic clock, we can predict biological age using molecular genetic techniques. As a rule of thumb, genome-wide hypomethylation and CpG island hypermethylation correlate with ageing, although this effect is tissue-specific5. 

Telomeres are regions of repetitive DNA at the terminal ends of linear chromosomes. Telomeres become shorter every time a cell divides (see Figure 2), and eventually, this can hinder their function of protecting the ends of chromosomes. As a result, cells have complex mechanisms in place to prevent telomere degradation. One of these is the enzyme telomerase, which maintains telomere length by adding G-rich DNA sequences. Another mechanism is the shelterin complex, which binds to ‘TTAGGG’ telomeric repeats to prevent degradation. Two major components of the shelterin complex are TRF1 and TRF2, which bind telomeric DNA. They are regulated by the chromatin remodelling enzyme BRM-SWI/SNF, which has been shown to be crucial in promoting genomic stability, preventing cell apoptosis, and maintaining telomeric integrity. BRM-SWI/SNF regulates TRF1/2, thereby, regulating the shelterin complex, by remodelling the TRF1/2 promoter region to convert it to euchromatin and increase transcription. BRM-SWI/SNF inactivating mutations have been shown to contribute to cancer and cellular ageing through telomere degradation6. Together, the mechanisms cells have in place to protect telomeres provide protection against cancer as well as cellular ageing. 

Future of anti-ageing drugs

Anti-ageing drugs are big business in the biotechnology and cosmetics sector. For example, senolytics are compounds that decrease the number of senescent cells in an individual. Senescent cells are those that have permanently exited the cell cycle and now secrete pro-inflammatory molecules (see Figure 3); they are a major cause of cellular and organismal ageing. Senolytic drugs aim to provide anti-ageing benefits to an individual, whereby senescent cells are removed, therefore, decreasing inflammation. Currently, researchers are certain that removing senescent cells would have an anti-ageing effect, although senolytic drugs currently on the market are understudied, and so their side effects are unknown. Speculative drugs could include those that enhance telomerase or SIRT1 activity.

Evidently, ageing is not purely determined by lifestyle and environmental factors alone but also by genetics. While longevity genes are hereditary, epigenetic modifications may be influenced by external factors. Therefore, we can attribute the complex interplay between various external factors and an individual’s genome to understanding the role of genetics in ageing. Perhaps we will see a new wave of anti-ageing treatments in the coming years, developed on the genetics of ageing. 

Written by Malintha Hewa Batage

Related articles: An introduction to epigenetics / Schizophrenia, inflammation and ageing

REFERENCES

Cilic, U et al., (2015) ‘A Remarkable Age-Related Increase in SIRT1 Protein Expression against Oxidative Stress in Elderly: SIRT1 Gene Variants and Longevity in Human’, PLoS One, 10(3).

Alcendor, R et al., (2004) ‘Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes’, Circulation Research, 95(10):971-80.

Alcendor, R et al., (2007) ‘Sirt1 regulates aging and resistance to oxidative stress in the heart’, Circulation Research, 100(10):1512-21.

Yin, Y & Wang, Z, (2018) ‘ApoE and Neurodegenerative Diseases in Aging’, Advances in Experimental Medicine and Biology, 1086:77-92. 

Wang, K et al., (2022) ‘Epigenetic regulation of aging: implications for interventions of aging and diseases’, Signal Transduction and Targeted Therapy, 7(1):374.

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