Biological differences between males and females extend seamlessly to the aging process. Globally, women have an average life expectancy approximately 5 years longer than men. Aging-related diseases also impact the two sexes unequally: for instance, men reach a 2% incidence rate of coronary heart disease roughly 10.1 years earlier than women, while women account for nearly two-thirds of all Alzheimer’s disease patients.
For decades, the scientific community has been investigating the root causes of sex-based differences in aging. A recent study published in Nature offers a new explanation rooted in sex chromosomes: SIRT7, a member of the longevity protein family, acts “preferentially” to protect the female X chromosome. When this protein is deficient, females face more severe health deterioration and shortened lifespan compared to males.
SIRT7: A Sex-Biased Member of the Longevity Protein Family
The sirtuin family of longevity proteins has long been a focal point in aging research. Comprising seven members (SIRT1 through SIRT7), they are widely involved in regulating cellular stress responses and metabolism, and are closely linked to the aging process.
Interestingly, multiple members of this family exhibit pronounced sex differences. SIRT2 deficiency predisposes male and female mice to different types of tumors; SIRT6 overexpression extends lifespan in male mice but has virtually no effect on females.
For this study, the research team focused on SIRT7. They developed SIRT7 knockout mice and discovered that this protein also displays sex-specific effects.
Male mice lacking SIRT7 had a median lifespan of 17.6 months, while females lived only 15.5 months. Female mice developed fatal megaesophagus — the primary cause of death in 77.3% of SIRT7-deficient mice — at an earlier age, and 4.6% of females developed bacterial enterocolitis, a condition that does not occur in males with the same genetic deficiency.
Why Does SIRT7 Deficiency Hit Females Harder? The Answer Lies in the Sex Chromosomes
The research team first set out to map the localization of SIRT7 protein. They found that in mouse embryonic fibroblast cells from females, up to 67% of SIRT7 binding sites are concentrated on the X chromosome; in male cells, by contrast, SIRT7 is significantly enriched on the Y chromosome.
This localization pattern suggests that the sex difference in SIRT7 function likely originates from the sex chromosomes. In mammals, females have an XX sex chromosome configuration while males have XY. If all genes on both X chromosomes were fully expressed, the output of X-linked genes in females would far exceed that in males. To prevent this dosage imbalance, mammals have evolved a dosage compensation mechanism.
In female cells, one of the two X chromosomes is randomly inactivated (Xi), ensuring that males and females have roughly the same number of active X-linked genes. The remaining active X chromosome (Xa), meanwhile, undergoes global transcriptional upregulation to match the expression level of autosomal genes. The coordinated function of the two X chromosomes relies on SIRT7 as a key regulator.
On the active X chromosome, SIRT7 “throttles” transcriptional activity by removing the H3K36ac mark — a marker of active transcription — to prevent overactivation. On the inactive X chromosome, SIRT7 restricts the expression of Xist RNA, the molecule that initiates X chromosome inactivation, thereby preventing excessive accumulation of the repressive mark H3K27me3 and avoiding overly tight silencing. In short, SIRT7 ensures neither X chromosome veers to an extreme.
When SIRT7 is depleted, this balance breaks down. Both X chromosomes malfunction simultaneously: the active X becomes overactive, structurally disorganized, and accumulates DNA damage; the inactive X becomes more tightly compacted and deeply silenced. This is why the same genetic defect exacts a higher toll on females than on males.
Why Do Some Aging-Related Diseases Affect More Women?
SIRT7 plays such a critical role on the X chromosome — but what about its function on other chromosomes?
On autosomes, SIRT7 is involved in basic cellular functions such as ribosomal RNA transcription and DNA damage repair. These processes occur in cells of both sexes and are unlikely to directly drive sex differences. As for the Y chromosome, this study only found that SIRT7 is significantly enriched there in males; its specific function remains to be further explored.
Taken together, current findings indicate that the sex-specific effects of SIRT7 stem from its unique role in regulating the female X chromosome. Could this also explain why certain aging-related diseases are more prevalent in women?
Approximately 15–25% of genes on the human X chromosome escape inactivation and remain expressed on the otherwise silent X chromosome. Some of these escape genes have been linked to aging-related diseases: 22 are associated with Aβ pathology in Alzheimer’s disease (20 of which are female-specific), and 49 are linked to tau protein pathology (43 of which are female-specific). Additionally, when immune-related genes are overexpressed due to escape from inactivation, they can overactivate immune pathways and trigger autoimmune diseases.
Therefore, if the mechanism uncovered in this study holds true in humans, dysregulation of the X chromosome caused by SIRT7 dysfunction could further destabilize genes that already tend to escape inactivation, potentially raising the risk of aging-related diseases.
Sex: A Variable That Cannot Be Ignored in Anti-Aging Interventions
These sex-based differences also permeate anti-aging interventions. Rapamycin delivers greater lifespan extension in female mice than in males; corylin, an extract from traditional Chinese medicine, extends female mouse lifespan by 11.9% but yields no benefit in males.
Among these interventions, NAD+ supplements deserve particular attention. Research has found that after 28 consecutive days of NAD+ complex supplementation, aging-related symptoms in women improved significantly, while men showed almost no change. As SIRT7 is an NAD+-dependent deacetylase, boosting NAD+ levels effectively provides functional support for SIRT7 — which may be one potential explanation for this observed sex difference.
In reality, the causes of sex differences in aging are far from limited to a single mechanism. Exclusive female protection from estrogen, differences in telomere attrition rate (generally faster in men), and disparities in mitochondrial function (men typically exhibit higher levels of oxidative stress) — among many other factors — collectively shape the distinct aging trajectories of men and women.
For women, if this regulatory mechanism of SIRT7 also applies to humans, it represents both an advantage and a vulnerability. Lifestyle factors that deplete NAD+ or increase oxidative stress — such as high-sugar diets, sedentary behavior and frequent late nights — could theoretically impair SIRT7 function indirectly, inflicting greater harm on women.
All in all, ongoing research into sex differences in aging is not about creating division, but about developing more precise and effective anti-aging strategies tailored to different sexes