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The State Of: Genomics in Aging

Aging is a natural and inevitable part of life, but the way we age and the traits we typically associate with this biological process are not necessarily guaranteed. In recent decades, life expectancy in most parts of the world has increased dramatically. Consequently, more is now known about the mechanisms that lead to aging and age-related disease. In this feature, we take a look at the past, present and future of aging research and the role of genomics in the field, to give you a comprehensive view of this scientific landscape.

The past

Increasing age is an inevitable part of life, and our image of the typical elderly person tends to incorporate mobility issues, weakness and even dementia. But these symptoms do not have to occur, and our definition of ‘elderly’ is dynamic and ever-changing. In fact, between 2000-2019, global life expectancy increased by over 6 years. And in the UK, girls born today can expect to live until the age of 83. These global increases are primarily driven through decreasing infant mortality, but the ability to treat previously lethal diseases, such as various cancers, has also contributed.

However, many global healthcare systems are struggling with increased life expectancy, due to the growing need for medical assistance in old age. As the percentage of a population that is over the age of 65 increases, there is a mounting strain on the health system. Additionally, if a higher proportion of the population is retired, this means that the level of funding for health systems via taxation will not meet demand. This means that we must find new ways to combat the impact of aging.

Having an understanding of the molecular and genetic basis of age-related conditions, and the mechanisms that underpin the process of aging itself, are crucial to addressing these problems. This began almost 100 years ago with the discovery of telomeres in the 1930s. This finding was integral to our understanding of chromosomal changes over time, before it was even known that DNA was the basis of genetic material.

Telomeres are repetitive structures that protect the ends of chromosomes. However, these structures shorten over time, primarily due to what is known as the end replication problem.  They can also shorten over time from accumulative oxidative damage. Hence, chromosomes find themselves with shorter and shorter telomeres, leading to damage and instability. The mutations associated with this, and other mutations that simply accrue over time due to, for example, UV exposure, lead to cellular senescence (a form of cell cycle arrest) and a number of age-related health problems such as cancer. Furthermore, in the early 1960s, it was revealed that cells could only replicate on average 50 times before becoming senescent – this number is known as the Hayflick limit.

There are also a number of genetic variations known to drive aging processes and many more that promote the onset of diseases typically seen in the elderly, such as dementia. The accumulation of these factors results in what we view as a typical ‘aged’ phenotype. Whilst this outcome may seem inevitable, there is mounting evidence that shows that biological aging and chronological aging do not necessarily need to go hand in hand. Combatting chromosomal instability and telomere shortening could in theory prevent cellular senescence and the associated side effects, something that is supported by evidence in those with advanced aging disorders, who appear to have shorter telomeres at a younger age.

As with many fields, the use of genomics and other omics are emerging as vital tools to understand the aging process. Given the heterogenous nature of cellular aging, single-cell and spatial techniques are key in understanding more about longevity at the molecular level. Gene expression changes that can be assessed via transcriptomics and proteomics have also recently been implicated in the process. Even lesser-used metabolomics techniques hasve been employed to identify changes in organisms over time.

The present

The world of aging research is dynamic and encompasses not only the fundamentals of telomeres, chromosomal instability and cellular senescence, but also age-related illnesses such as dementia and Parkinson’s disease. Below, we explore some ground-breaking research from the last 12 months.

Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging: This study from August 2023 assessed the genomes of 1.9 million individuals of European ancestry, finding 52 variants associated with age-related phenotypes. The study also focussed on drug target identification, revealing 122 loci that could be targeted for healthy aging (Rosoff et al., 2023).

Genome-wide RNA polymerase stalling shapes the transcriptome during aging: From early 2023, this study combined RNA sequencing with ChIP-seq to uncover the mechanisms underpinning age-related gene expression changes. The authors discovered that the ‘aging transcriptome’ is formed due to RNA polymerase stalling, which leads to transcriptional stress (Gyenis et al., 2023).

Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity: This study assessed the impact of metformin use on aging; the drug has previously been shown to increase longevity. By assessing DNA methylation data, the researchers discovered that an epigenetic mechanism may be responsible for this effect (Marra et al., 2023).

Artificial intelligence for dementia genetics and omics: This recent review identified key challenges that remain in Alzheimer’s and dementia research. It explored how not only genomics and other omics can address these problems, but also how the role of artificial intelligence can enhance these findings (Bettencourt et al., 2023).

Genome-wide profiling of circulatory microRNAs associated with cognition and dementia: Another dementia-focussed study, the authors of this paper investigated the role of circulating micro-RNAs in dementia and cognition. They found that four of these micro-RNAs are associated with this age-related phenotype (Taqub et al., 2023).

DNA methylation signature of aging: potential impact on the pathogenesis of Parkinson’s disease: Published in January 2023, this study explored the idea that DNA methylation changes contribute to aging and in particular to the pathogenesis of Parkinson’s disease. The authors present a comprehensive analysis of the methylation of both diseased and healthy brains (Volkan et al., 2023).

Considerations for reproducible omics in aging research: This review focused on the challenges associated with using multi-omics in aging research, explored best practices for robustness and reproducibility and suggests general guidelines for experimental design (Singh and Benayoun, 2023).

Thymidine nucleotide metabolism controls human telomere length: In order to elucidate the genetic mechanisms underpinning telomere length, the authors of this study performed a large-scale CRISPR-Cas9 screen and revealed that thymidine nucleotide metabolism plays an integral role in human telomere maintenance (Mannherz and Agarwal, 2023).

Aging is associated with a systemic length-associated transcriptome imbalance: One from late-2022, this meta-analysis published in Nature Aging looked at age-resolved transcriptome data and demonstrated that transcript length explains most of the age-related transcriptome changes in humans (Stoeger et al., 2022).

Metabolomics in aging research: aging markers from organs: A review from June 2023, the authors of this paper assessed research from the last ten years to identify metabolomic changes associated with aging (Fang et al., 2023).

In the spotlight

Telomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1 – Smoom et al., 2023.

The commonly used research mouse, Mus musculus, has telomeres that are up to five times longer than a human’s, meaning that aging cannot be accurately modelled in this animal. Biological studies are less commonly explored in other kinds of model, and so telomere research has suffered in this regard. Given the popularity of Mus musculus in research and the resources invested in making this an effective model, it is vital to find a way to efficiently study aging in the rodent.

Another type of mouse that is less commonly used in research, Mus spretus, has shorter telomeres, closer in length to that of a human. The researchers tracked the cause down to a single mutation in the helicase core of the RTEL1 gene; this leads to a lysine appearing at position 492 in Mus spretus, compared to methionine in both humans and Mus musculus. By inducing this mutation in Mus musculus models using CRISPR-Cas9, the telomeres were shortened. This means that more aging and telomere studies could be carried out in labs that are set up to use this common specimen, potentially leading to advancements for cellular senescence research.

Figure 1: Diagram showing the structure of the mouse RTEL1 gene and the methionine to lysine switch that occurs in Mus spretus. Adapted from Smoom et al., 2023.

Additionally, the researchers developed a method to measure the lengths of individual telomeres, even very short ones. They dubbed this method ‘NanoTelSeq’, a new technology that could further transform the landscape of aging research.

From FLG

Back in May, we had the pleasure of hosting a webinar titled ‘Unlocking the Power of Gene Expression Reprogramming to Reverse Chronic Age-Related Diseases.’ During this webinar, we were joined by three expert speakers (Aubrey De Grey (LEV Foundation), Axel Martinelli (Big Omics) and Salah Mahmoudi (Alkahest)) who discussed the latest insights into the Robust Mouse Rejuvenation programme and implications for late-onset intervention to reverse ageing, how to leverage existing datasets to gain a better understanding of age-related disorders and potentially unlock novel targets, and how the plasma proteome changes with age and is leading to the development of novel therapies. Our speakers also provided examples to showcase these ideas.

To watch the webinar, click here.

The future

The rise of new omics technologies will continue to transform the aging landscape – as it has done for so many fields. In particular, the growth of lesser used omics such as metabolomics will likely lead to new insights into this inevitable biological process. It is hard to say whether true cures will be found for the age-related diseases discussed above, but the discovery and implementation of preventative and ameliorating measures is almost inevitable.

Focus has shifted from understanding aging as a whole, to trying to increase longevity, to trying to ensure that the aging process occurs in a healthy manner. It is believed that the number of over 60s will increase from 900 million to over 2 billion by 2050, so ensuring that older people continue to have a high quality of life is vital. Alongside the use of new technologies to understand the biological underpinnings of aging, the ethics of aging research must be strongly considered. The Nuffield Council on Bioethics has recently released a report detailing the ways in which these ethics can be considered going forward.

It is clear that the definition of the word elderly has dramatically changed and will continue to fluctuate. In the years ahead, we must strive to understand the why and how of aging, and ensure that we can guarantee the health and wellbeing of a large percentage of our population.

References and further reading

Wheeler, H.E. and Kim, S.K., 2011. Genetics and genomics of human ageing. Philosophical Transactions of the Royal Society B: Biological Sciences, 366(1561), pp.43-50.

Deelen, J., Beekman, M., Capri, M., Franceschi, C. and Slagboom, P.E., 2013. Identifying the genomic determinants of aging and longevity in human population studies: progress and challenges. Bioessays, 35(4), pp.386-396.

de Magalhães, J.P., Lagger, C. and Tacutu, R., 2021. Integrative genomics of aging. In Handbook of the Biology of Aging (pp. 151-171). Academic Press.

Lorusso, J.S., Sviderskiy, O.A. and Labunskyy, V.M., 2018. Emerging omics approaches in aging research. Antioxidants & Redox Signaling29(10), pp.985-1002.

Shokhirev, M.N. and Johnson, A.A., 2021. Modeling the human aging transcriptome across tissues, health status, and sex. Aging cell20(1), p.e13280.

More on these topics

Aging / Genomics / Multi-omics / Precision Medicine