While we can list many differences between males and females, how we age is usually not one we think of. Globally, females live longer than males- the average life expectancy of females in 2021 was 73.8 years, compared to 68.4 years for males. Life expectancy is altered by the mortality rates of all age groups. For instance, males have a higher chance of being born prematurely, as well as passing away during the first week of life.

In addition, although the mortality rates of both sexes increase with age due to many diseases, such as cancer and cardiovascular disease (CVD), males still maintain a higher mortality rate in later stages of life. In 2021, according to the Human Mortality Database, all countries had a higher mortality rate for males over 65 versus females over 65. Is this disparity in life expectancy simply due to differences in lifestyle, or is there some underlying biological explanation?

There are various biological factors that influence sex-specific aging, including sex chromosomal-linked mechanisms. While females have two copies of the X chromosome, males have only one copy, along with a Y chromosome. Due to this, males are more likely to be afflicted with X-linked recessive diseases such as the blood clotting disorder, hemophilia.

Sex hormones constitute another key biological factor that impacts the aging process in males and females. The main sex hormones are testosterone, estrogen hormones (estradiol, estriol, and estrone), and progesterone. Testosterone is abundant in males, while estrogen and progesterone are mainly found in females.

How can having differing sex hormones dictate how we age? As males and females age, changes in their sex hormone levels occur, which may result in negative health effects. Females normally undergo menopause in their 40s or 50s, due to a decline in production of estrogen and progesterone. During this time, there is a decrease in muscle mass, strength and bone mass density, and an increase in visceral fat. Reduced muscle strength can cause general mobility impairments, such as difficulty getting up from sitting, climbing stairs, and walking.

Before menopause, females are less likely to develop CVD, which is the leading cause of death worldwide. This is partly because estrogen plays a protective role against CVD. Estradiol has been found to increase the development of new blood vessels referred to as angiogenesis, vasodilation, and decrease fibrosis, which is the scarring of tissue. Once menopause occurs, the decline in estrogen is linked to an increase in CVD risk in females.

Males also have a decline in testosterone in andropause, which is the male equivalent of menopause. However, this decline in sex hormones is much less drastic than in females, with there normally being a 1% decrease per year. In males who are older than 60, relatively lower testosterone levels are linked to a higher chance of developing osteoporosis, rapid loss of hip bone density, as well as hip and nonvertebral fractures. Low testosterone levels also cause a decrease in muscle mass, leading to a decline in muscle strength. This results in multiple health complications, including balance disorders, an increased risk of falling, obesity, and type 2 diabetes.

Additionally, sex hormones impact immune function. Females tend to have stronger innate and adaptive immune responses in comparison to males. This results in females being better prepared to tackle pathogens. For example, compared to males, females have a superior antibody response to antigens, as well as a greater number of B cells. However, this heightened immune activation is a double-edged sword, also rendering females more susceptible to developing autoimmune diseases, such as the chronic neuroinflammatory disease, multiple sclerosis.

Sex-specific patterns exist in other age-related diseases as well, such as in Alzheimer’s disease (AD). AD is an irrecoverable disease where brain cells are slowly destroyed, resulting in memory loss and cognitive decline. Around two-thirds of Americans who have AD are females. There are differences in the pathology of AD between sexes. Studies have found that females have a greaterloss in brain volumeand a larger decline in cognitive function. An important risk factor for AD is the expression of the apolipoprotein E4 gene (APOE4), which generates a protein involved in cholesterol transportation. Females with APOE4 tend to have a higher risk than males expressing APOE4 of developing AD.

Another notable age-related disease is osteoarthritis, where there is irreversible degeneration of the cartilage that cushions the ends of bones inside joints. This condition usually affects joints in the knees, hands, hips, and spine, causing pain, swelling, and joint stiffness. This disease is more prevalent, and with higher severity, in females. Many women start developing age-related disease symptoms after menopause, which could be linked to the decrease in estrogen that occurs during this period.

Given that all these negative health outcomes are more common in aging females versus males, it seems that females suffer from greater rates of disability and worse health as they age, despite, on average, having a longer life expectancy than males. This phenomenon is referred to as the male-female health-survival paradox. Males are normally healthier than females at the time of death, despite dying younger. Further research on how each sex ages and develops diseases will allow for more targeted approaches to ensure healthy aging and longevity in the entire population, while delaying onset of debilitating diseases.


References 

Alberts, S. C., E. A. Archie, L. R. Gesquiere, J. Altmann, J. W. Vaupel, and K. Christensen. 2014. The Male-Female Health-Survival Paradox: A Comparative Perspective on Sex Differences in Aging and Mortality. In Sociality, Hierarchy, Health: Comparative Biodemography: A Collection of Papers. National Academies Press (US).  

Altmann, A., L. Tian, V. W. Henderson, and M. D. Greicius. 2014. Sex modifies the apoe‐related risk of developing alzheimer disease. Annals of Neurology 75: 563–573.  

Fink, A. L., and S. L. Klein. 2018. The evolution of greater humoral immunity in females than males: Implications for vaccine efficacy. Current Opinion in Physiology 6: 16–20.  

Hägg, S., and J. Jylhävä. 2021. Sex differences in biological aging with a focus on human studies. eLife 10.  

Hame, S. L., and R. A. Alexander. 2013. Knee osteoarthritis in women. Current Reviews in Musculoskeletal Medicine 6: 182–187.  

Hinderer, S., and K. Schenke-Layland. 2019. Cardiac fibrosis – a short review of causes and therapeutic strategies. Advanced Drug Delivery Reviews 146: 77–82.  

Horstman, A. M., E. L. Dillon, R. J. Urban, and M. Sheffield-Moore. 2012. The role of androgens and estrogens on healthy aging and longevity. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 67: 1140–1152.  

Iorga, A., C. M. Cunningham, S. Moazeni, G. Ruffenach, S. Umar, and M. Eghbali. 2017. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of Estrogen therapy. Biology of Sex Differences 8: 33.  

Kolahchi, Z., N. Henkel, M. A. Eladawi, E. C. Villarreal, P. Kandimalla, A. Lundh, R. E. McCullumsmith, and E. Cuevas. 2024. Sex and gender differences in alzheimer’s disease: Genetic, hormonal, and inflammation impacts. International Journal of Molecular Sciences 25: 8485.  

Maltais, M. L., Desroches, J., and I. J. Dionne. 2009. Changes in muscle mass and strength after menopause. Journal of musculoskeletal & neuronal interactions 9: 186–197. 

Menopause https://www.mayoclinic.org/diseases-conditions/menopause/symptoms-causes/syc-20353397  

Mielke, M., P. Vemuri, and W. Rocca. 2014. Clinical epidemiology of alzheimer’s disease: Assessing sex and gender differences. Clinical Epidemiology 37.  

Osteoarthritis https://www.mayoclinic.org/diseases-conditions/osteoarthritis/symptoms-causes/syc-20351925  

Osteoarthritis https://www.niams.nih.gov/health-topics/osteoarthritis  

Reproductive hormones https://www.endocrine.org/patient-engagement/endocrine-library/hormones-and-endocrine-function/reproductive-hormones#:~:text=The%20main%20reproductive%20hormones%20estrogen,and%20testes%20(in%20males)  

Ryczkowska, K., W. Adach, K. Janikowski, M. Banach, and A. Bielecka-Dabrowa. 2022. Menopause and Women’s Cardiovascular Health: Is it really an obvious relationship? Archives of Medical Science 19: 458–466.  

Sciarra, F., F. Campolo, E. Franceschini, F. Carlomagno, and M. Venneri. 2023. Gender-specific impact of sex hormones on the immune system. International Journal of Molecular Sciences 24: 6302.  

Why Does Alzheimer’s Affect More Women Than Men? https://www.brightfocus.org/alzheimers/article/why-does-alzheimers-disease-affect-more-women-men 

What is Alzheimer’s disease? https://alzheimer.ca/en/about-dementia/what-alzheimers-disease 

Why do women live longer than men? https://ourworldindata.org/why-do-women-live-longer-than-men  

Zhu, D., A. Montagne, and Z. Zhao. 2021. Alzheimer’s pathogenic mechanisms and underlying sex difference. Cellular and Molecular Life Sciences 78: 4907–4920.  

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Faizah Numa Sayeed

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