Living forever? It’s written in your DNA.

The prospect of being immortal might be closer than we think.

Writer: Maja Bronowska 
Editor: Dan Jacobson
Artist: Zach Ng

The idea of living forever may sound insane. There is no doubt that we age, and that our biological functions decline leading, eventually, to death. Human life expectancy has extended enormously and continues to increase, but is there a limit? The answer is unclear. The oldest documented human, Jeanne Calment, lived for 122 years and 164 days, dying in 1997. For over two decades, this record has persisted. In general, human longevity records no longer increase, as if having reached a plateau.

Undeniably, our society is ageing. It is estimated that by 2037, 1.37 billion households will be headed by someone 85 years old or older, an increase of 161% from now. As a consequence, this will drive up health and social healthcare costs, increasing the burden on taxpayers and the care system. With age, biological functions decline and societal roles change. Moreover, avoiding environmental diseases and improving chronic health conditions cannot extend longevity forever. The real culprit that must be overcome is ageing itself.   

The blueprint of ageing is held within DNA, and so the maximum achievable age is mostly determined by genetics. Using genomic techniques such as next-generation sequencing, gene variants of APOE and FOXO3A were found to be highly associated with longevity in humans. The APOE gene is associated with Alzheimer’s disease whereas FOXO3A was found to play an important role in carcinogenesis. However, the suggestion that these two genes alone are the strongest drivers of longevity in humans remains controversial. Ageing is more likely the product of complex interactions between many genes. 

Furthermore, genomic stability plays an important role in ageing. Stability depends on DNA integrity, which is maintained by DNA repair mechanisms. This supports the proposition that it is the interaction of many genes, rather than a handful, that is responsible for ageing. Nonetheless, gene expression is not solely genetic, but is a combination of both genes and environmental factors. Epigenetics, the study of how environmental factors alter gene expression, is quickly becoming an essential area of knowledge in science, allowing us to understand more about patterns of gene expression and how they are regulated.

Ageing is likely linked to epigenetic alterations, particularly DNA methylation. At cytosine-phosphate-guanine (CpG) DNA sites, methyl groups covalently bind to cytosine, leading to altered expression of genes, including those that are critical for ageing, without altering the original DNA sequence. These methylation patterns change with age and can be considered as ‘clock’ biomarkers that track ageing with high accuracy.

In 2019, Benjamin Mayne and colleagues carried out a study in which they analysed the density of CpG sites in the genomes of vertebrates with established lifespans. CpG islands are prone to mutations, suggesting that they may be involved in evolutionary processes. They found that 42 gene promoters can be used as effective biomarkers to assess and predict the lifespans of different species.

Surprisingly, for humans, the lifespan clock is estimated at 38 years. Analysing trends in life expectancy and late-life survival, we see that women tend to live longer, but there is a sharp decline after the age of 80. Ageing can be considered as a series of pre-programmed events to enforce natural selection, but, in the case of humans with advanced medicine at our disposal, this is no longer the case.

In particular, our understanding of epigenetics has improved enormously. Epigenetic aberrations responsible for genomic instability in cancer patients are now targetable. New generations of drugs that are highly selective are entering clinical development phases. Once we master this, it might be a matter of time before the same approach is applied to ageing. Some pharmaceutical interventions have already been demonstrated to improve life expectancy, so the possibility of altering gene sequences is even more promising ‒ particularly with adeno-associated viruses or CRISPR/Cas9 systems.

Together with advances in science and our understanding of longevity, ethical considerations are also being raised. Many scientists point out that immortality poses a threat to our society. The overpopulation crisis may lead to shortage of resources. ‘Life extension’ technologies are likely to be expensive, making them a luxury for the wealthy and exacerbating inequality.

The idea of clipping genes that reduce our longevity and introducing alleles that can extend our lifespan is tempting. As for today, it is not possible yet, but it is not too distant a reality. New technologies are emerging and gene editing technologies are developing faster than we may expect. Thus, the way we think about life and death is soon to be changed. Naturally, we want to keep on extending our lifespan, but the remaining question is: who wants to live forever?

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