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Wisdom of ageing: What can we learn from Centenarian genomes?

By Delbert Almerick Tan Boncan and Dr Vince Vardhanabhuti


Genome-wide association studies (GWAS) identify the associations of genotypes with phenotypes across many genomes by testing the allele frequency of genetic variants between individuals who are related by descent but differ phenotypically. GWAS leverages single-nucleotide polymorphisms (SNPs, pronounced “snips”), apart from copy-number variations (CNV) and sequence variations, to study the functions of genetic variation in the human genome. In GWAS, genomic risk loci represent blocks of SNPs with significant association with a trait or disease of intrest. In turn, these genomic risk loci (scores) – and its extension polygenic risk scores (PRSs) – can be used as stratification tools and genetically based biomarkers. The statistical robustness of GWAS results has paved the way to gaining insights into a phenotype’s underlying biology, estimating its heritability, calculating genetic correlations, making clinical risk predictions, and inferring potential causal relationships between risk factors and health outcomes among others [1].


SNPs are a DNA sequence variation (or mutation) that occurs when a single nucleotide (from any of the four DNA alphabets: Adenine, Thymine, Guanine and Cytosine) in the genome is altered and when that particular alteration is present in at least 1% of the population [2]. While most if not all of them are non-deleterious, SNPs can occur in genic (exonic or intronic), intergenic and regulatory regions of the genome as silent or missense mutations causing no change or [VV1] [BDAT2] subtle changes in gene regulation, in how proteins work or in the way cells behave. Therefore, SNPs serve as one of the molecular bases of individual differences. SNPs make up about 90% of all human genetic variation where there is one (1) SNP for every 300 bases along the 3-billion-base human genome [3]. There are a number of techniques, from microarrays to high-throughput sequencing, used to understand how SNPs predispose people to certain diseases and the influence they have on varying therapeutic responses of individuals.


The compression of morbidity is one important aspect that is often associated with a longevity society [4]. While an increasing lifespan indicates improving healthcare, it is equally important to address how healthspan lags behind by asking what genetic variants potentially confer exceptional healthspan and lifespan of those who live to very old age such as centenarians – i.e. individuals at or who have surpassed the age of 100 yet appear to be in both good physical and mental condition. Do they simply carry no “pathogenic” variants or are they endowed with rare “longevity” variants? Much of what is known is limited to only two genes: APOE and FOXO3A. These two genes have been shown to be associated with longevity in nearly all studies [5]–[7]. APOE or the apolipoprotein E comprise a group of lipid transporters (including cholesterol and other fats) in the bloodstream. APOE alleles (gene variants) are known to be associated with extreme longevity – alleles e2 and e3. Interestingly, the e4 allele appears to be an antithesis of the APOE longevity alleles – where it is associated with an increased risk of cardiovascular diseases and Alzheimer’s disease. On the other hand, the Forkhead/winged helix box genes or FoxO proteins are a set of evolutionarily conserved transcription factors (proteins that initiate gene expression) that regulate important cellular functions yet are often dysregulated in cancer cells. The roles of FOXO3 in longevity may involve the upregulation of target genes involved in stress resistance, metabolism, cell cycle arrest and apoptosis [7]. A meta-analysis study [8] shows SNPs near CADM2 (Cell Adhesion Molecule 2) and GRIK2 (Glutamate Ionotropic Receptor Kainate Type Subunit 2) that appear to be associated with longevity, while new longevity loci continue to be discovered from different cohorts [9] and from different approaches [10].


One study employing whole-exome sequencing on two (2) cohorts of Ashkenzi Jewish participants shows that centenarians have a similar number of pathogenic rare coding variants to control individuals – suggesting that rare variants detected in the conserved ageing pathways are protective against age-related pathology [11]. Grouping the variants within the same gene, or genes in the same pathway, centenarians appeared to carry more variants in genes involved in insulin/insulin receptor and AMPK (AMP-activated protein kinase) signalling pathways – pathways that are involved in carbohydrate and fat metabolism. How do these rare variants confer longevity? Referring back to APOE, the major allele (gene variant that exists in the human population) is e3, but the presence of the allele e4 (APOE4) increases the risk of Alzheimer’s and cardiovascular diseases [6]. Carriers of APOE4 have been observed to die at a younger age than non-carriers. So, what does this have to do with the rare variants found in centenarians? The presence of these rare “protective” variants (involved in the insulin and AMPK signalling pathways) appear to not only extend the longevity of APOE4 non-carriers, but they were also found to provide protective function by delaying the debilitating effect of APOE4 on carriers adding 9 more years compared with APOE4 carriers without such rare variants. Although it is not clear what these variants are doing to the genes involved in the two metabolic pathways, it can be speculated that the effect is translated down to the protein level – which counters the effect of an existing pathology – since the variants are found in the gene bodies or they are exonic in origin (e.g., ABCA1/cholesterol efflux regulatory protein, PLCG2/phospholipase C gamma 2). Another similar study shows rare “protective” variants that reside on chromosome 4 (ELOVL6/fatty acid elongase 6) and chromosome 7 (USP42/ubiquitin specific peptidase 42) [12]. These underscore the importance of studying truly rare survival to identify common and rare variants associated with extreme longevity and longer healthspan.


The success of GWAS in understanding the genetic basis of longevity is largely hindered by the rarity of longevity phenotype wherein the extreme rarity of centenarians in human populations essentially constrains the possibility of performing the large studies necessary to discover rare variants through statistically significant genetic associations [11]. Furthermore, the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. Looking into the genomes of families with a known history of longevity provides a small yet alternative cohort for uncovering protective alleles and associated biological signatures for healthy ageing and longevity [5]. With fast-paced developments in both DNA assay technologies and statistical methodologies, we have yet to realise the full potential of SNP-based markers in GWAS in uncovering the mysteries of longevity.


References:

[1] E. Uffelmann et al., “Genome-wide association studies,” Nature Reviews Methods Primers 2021 1:1, vol. 1, no. 1, pp. 1–21, Aug. 2021, doi: 10.1038/s43586-021-00056-9.

[2] A. Auton et al., “A global reference for human genetic variation,” Nature, vol. 526, no. 7571, p. 68, Sep. 2015, doi: 10.1038/NATURE15393.

[3] M. R. Nelson et al., “Large-Scale Validation of Single Nucleotide Polymorphisms in Gene Regions,” Genome Research, vol. 14, no. 8, p. 1664, Aug. 2004, doi: 10.1101/GR.2421604.

[4] A. Garmany, S. Yamada, and A. Terzic, “Longevity leap: mind the healthspan gap,” npj Regenerative Medicine, vol. 6, no. 1, p. 57, Dec. 2021, doi: 10.1038/s41536-021-00169-5.

[5] C. Caruso et al., “How Important Are Genes to Achieve Longevity?,” International Journal of Molecular Sciences 2022, Vol. 23, Page 5635, vol. 23, no. 10, p. 5635, May 2022, doi: 10.3390/IJMS23105635.

[6] P. Sebastiani et al., “APOE Alleles and Extreme Human Longevity,” The Journals of Gerontology: Series A, vol. 74, no. 1, pp. 44–51, Jan. 2019, doi: 10.1093/GERONA/GLY174.

[7] B. J. Morris, D. C. Willcox, T. A. Donlon, and B. J. Willcox, “FOXO3: A Major Gene for Human Longevity - A Mini-Review,” Gerontology, vol. 61, no. 6, pp. 515–525, Oct. 2015, doi: 10.1159/000375235.

[8] L. Broer et al., “GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy,” The Journals of Gerontology: Series A, vol. 70, no. 1, pp. 110–118, Jan. 2015, doi: 10.1093/GERONA/GLU166.

[9] X. Liu et al., “Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15,651 Chinese individuals,” Aging Cell, vol. 20, no. 3, p. e13323, Mar. 2021, doi: 10.1111/ACEL.13323.

[10] L. C. Pilling et al., “Human longevity: 25 genetic loci associated in 389,166 UK biobank participants,” Aging, vol. 9, no. 12, pp. 2504–2520, Dec. 2017, doi: 10.18632/aging.101334.

[11] J.-R. Lin et al., “Rare genetic coding variants associated with human longevity and protection against age-related diseases,” Nature Aging 2021 1:9, vol. 1, no. 9, pp. 783–794, Sep. 2021, doi: 10.1038/s43587-021-00108-5.

[12] P. Sebastiani et al., “Four Genome-Wide Association Studies Identify New Extreme Longevity Variants,” The Journals of Gerontology: Series A, vol. 72, no. 11, pp. 1453–1464, Oct. 2017, doi: 10.1093/GERONA/GLX027.


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