Sex as a biological variable in ageing: insights and perspectives on the molecular and cellular hallmarks

Abstract

Sex-specific differences in lifespan and ageing are observed in various species. In humans, women generally live longer but are frailer and suffer from different age-related diseases compared to men. The hallmarks of ageing, such as genomic instability, telomere attrition or loss of proteostasis, exhibit sex-specific patterns. Sex chromosomes and sex hormones, as well as the epigenetic regulation of the inactive X chromosome, have been shown to affect lifespan and age-related diseases. Here we review the current knowledge on the biological basis of sex-biased ageing. While our review is focused on humans, we also discuss examples of model organisms such as the mouse, fruit fly or the killifish. Understanding these molecular differences is crucial as the elderly population is expected to double worldwide by 2050, making sex-specific approaches in the diagnosis, treatment, therapeutic development and prevention of age-related diseases a pressing need.

Keywords: X chromosome; X-chromosome inactivation; ageing; hallmarks of ageing; sex chromosomes; sex hormones.

Figure 1.

Graphical illustration of the hallmarks of ageing and how they are affected in a sex-specific manner. One example per hallmark (green for females and yellow for males) is illustrated. Primary hallmarks are shaded in light blue. Chromosome instability results in Y chromosome loss in men and X chromosome loss in females. Telomere attrition is faster in males than females, in part due to the oestrogen responsiveness of the TERT subunit of the telomerase complex. Epigenetic alterations include hypermethylation of the Y chromosome and relaxation of the heterochromatic inactive X that leads to the upregulation of X-linked genes. Loss of proteostasis affects primarily males, where X-linked mutations reduce lifespan and influence disease onset. Disabled macroautophagy is female-biased with lower activity seen in osteoblasts and skeletal muscle. Antagonistic and integrative hallmarks are shaded in beige and light grey, respectively. Cellular senescence negatively affects males before females. Mitochondrial dysfunction affects males before females and is associated with impaired clearance of reactive oxygen species (ROS) and production of antioxidants. Nutrient sensing: sex effects depend on the modulation of each pathway. The example shows oestradiol, which improves glucose tolerance in males. Integrative hallmarks: Loss of stem cell potential is faster in males. Altered intercellular communication is illustrated by the increase in mitochondrial-derived microvesicles in female aged astrocytes. Inflammaging affects males more than females. Dysbiosis starts later in females, as menopause impacts microbial diversity.

Figure 2.

Artistic illustration of the opposing effects of the double X chromosome dosage in females. The biallelic expression of some genes on the second (and inactive) X chromosome in female mammals extends their lifespan and consequently, females celebrate more birthdays (right-hand plate). While their lifespan is longer, having that additional X chromosome comes at the expense of a worsened healthspan (frailty), and thus having a higher risk of autoimmunity and specific neurological disorders (left-hand plate).