The study of human longevity has long been a source of fascination for scientists, particularly in relation to the genetic factors that contribute to differences in lifespan between the sexes. One particularly intriguing area of research concerns the Y chromosome and its impact on male longevity. The Y chromosome expresses genes that are essential for male development and reproduction. However, it may also influence various physiological processes and health outcomes. It is therefore of great importance to investigate the impact of the Y chromosome on longevity. This may assist in elucidating the biological mechanisms underlying sex-specific differences in aging and disease susceptibility. As longevity research progresses, the Y chromosome's role presents a promising avenue for elucidating the complex interplay between genetics and aging.

Transposable elements (TEs), often referred to as "jumping genes", are DNA sequences that can move within the genome, potentially causing mutations and genomic instability. In young, healthy cells, various mechanisms, including DNA methylation and histone modifications, suppress TE activity to maintain genomic integrity. However, as individuals age, these regulatory mechanisms may deteriorate, leading to increased TE activity. This dysregulation could contribute to age-related genomic instability, cellular dysfunction, and the onset of diseases such as cancer. Understanding how TE repression changes with age is crucial for uncovering the molecular underpinnings of aging (De Cecco et al. 2013; Van Meter et al. 2014).

The lower recombination rates observed on Y chromosomes result in the accumulation of TE insertions, which in turn leads to an enrichment of TEs and potentially higher TE activity. To ascertain whether the number of Y chromosomes is associated with TE activity in humans, Teoli et al. (2024) studied the TE expression level, as a proxy of the TE activity, in several karyotype compositions (i.e. with differing numbers of Y chromosomes). They used transcriptomic data from blood samples collected in 24 individuals (six females 46,XX, six males 46,XY, eight males 47,XXY and four males 47,XYY). Even though they did not observe a significant correlation between the number of Y chromosomes and TE expression, their results suggest an impact of the presence of the Y chromosome on the overall TE expression. The presence of Y chromosomes also affected the type (family) of TE present/expressed. To ensure that the TE expression level was not biased by the expression of a gene in proximity due to intron retention or pervasive intragenic transcription, the authors also tested whether the TE expression variation observed between the different karyotypes could be explained by gene (i.e. here non-TE gene) expression. 

As TE repression mechanisms are known to decrease over time, the authors also tested whether TE repression is weaker in older individuals, which would support a compelling link between genomic stability and aging. They investigated the TE expression differently between males and females, hypothesizing that old males should exhibit a stronger TE activity than old females. Using selected 45 males (47,XY) and 35 females (46,XX) blood samples of various ages (from 20 to 70) from the Genotype-Tissue Expression (GTEx) project, the authors studied the effect of age on TE expression using 10-year range to group the study subjects. Based on these data, they fail to find an overall increase of TE expression in old males compared to old females.

Notwithstanding the small number of samples, the study is well-designed and innovative, and its findings are highly promising. It marks an initial step towards understanding the impact of Y-chromosome ‘toxicity’ on human longevity. Despite the relatively small sample size, which is a consequence of the difficulty of obtaining samples from individuals with sex chromosome aneuploidies, the results are highly intriguing and will be of interest to a broad range of biologists.

References

De Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J, Peterson AL, Kreiling JA, Neretti N, Sedivy JM (2013) Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell, 12, 247–256. https://doi.org/10.1111/acel.12047

Teoli J, Merenciano M, Fablet M, Necsulea A, Siqueira-de-Oliveira D, Brandulas-Cammarata A, Labalme A, Lejeune H, Lemaitre J-F, Gueyffier F,  Sanlaville D, Bardel C, Vieira C, Marais GAB, Plotton I (2024) Transposable element expression with variation in sex chromosome number supports a toxic Y effect on human longevity. bioRxiv, ver. 5 peer-reviewed and recommended by Peer Community in Genomics. https://doi.org/10.1101/2023.08.03.550779

Van Meter M, Kashyap M, Rezazadeh S, Geneva AJ, Morello TD, Seluanov A,  Gorbunova V (2014) SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nature Communications, 5, 5011. https://doi.org/10.1038/ncomms6011