Tied Up In Knots: Aging Affects Brain Stem Cell-Supplying Blood Vessels Sex-Specifically

Men are from Mars, women are from Venus. Although this saying captures that each gender is accustomed to its own set of emotional balances, cultures, and values — or, metaphorically, live on different planets — it does not explain why, with age, memory and cognitive function in males and females decline at different rates.

Analyzing 3D reconstructions of the brain and its associated vasculature at different points in the lifespan of mice, Zhao and colleagues discovered dramatic sex differences in the aging of the blood vessels that fuel a brain region responsible for regulating brain stem cell activity. Accompanying these vascular changes, males showed a significant decline in brain stem cell numbers, proliferation, and migration with age, whereas females did not. This study underscores the importance of addressing how aging creates sex-specific differences, indicating that the type of intervention required to treat brain health would likely vary with both sex and age.

The Subventricular Zone Harbors Brain Stem Cells

Pretty much smack in the middle of the brain is a region called the ventricular-subventricular zone (V-SVZ) that harbors brain stem cells. These cells are tasked with replenishing certain populations of neurons throughout life in the adult mouse brain. With age, there is a dramatic decline in the V-SVZ’s generation of new neurons accompanied by changes in the niche — an area of a tissue that provides a specific microenvironment, in which stem cells are present in an undifferentiated and self-renewable state.

Less well studied is the response of the specialized V-SVZ vasculature which, as in other stem cell niches, plays a vital role in supplying cells with nutrients and oxygen. Studies have shown that blood vessels in the V-SVZ niche preserve the pool of quiescent stem cells and promote proliferation and neurogenesis — the process by which new neurons are formed in the brain. But, these observations were made in aging males, so the response of the niche and neural stem cell lineage to aging in females is not known. Along these lines, how blood vessel parameters like diameter and tortuosity — the amount of twisting — change with age and sex have not been examined in the V-SVZ. 

Brain Stem Cell Vasculature Ages Sex-Specifically

Zhao and colleagues used techniques to reconstruct the V-SVZ in 3D from male and female mice at different life stages, creating a montage of V-SVZ sex-specific aging. Using an unbiased computer-based analysis enabled the researchers to address some long-standing and important questions regarding whether the niche is sexually dimorphic and whether aging influences sex differences in brain stem cell behavior and niche structure.

By examining the entire 3D niche, Zhao and colleagues found significant sex differences, with females being relatively spared through very old age. Females showed increased blood vessel diameter but decreased vessel density with age, while males showed decreased blood vessel diameter and increased tortuosity and vessel density. Specifically, V-SVZ vessel diameter decreased with age in males, but increased during late female mouse life, including the gain of a second population of larger capillaries. This resulted in aged males having much smaller vessel diameters than aged females.

Zhao and colleagues postulate that males and females may compensate for age-related vascular changes in different ways. They suggest that males may compensate for an age-associated increase in narrow, tortuous vessels by increasing density, while females may compensate for a decrease in density by increasing vessel diameter.

Brain Stem Cells Undergo Age- and Sex-Specific Changes

Besides blood flow, V-SVZ blood vessels guide the migration of brain stem cells. When Zhao and colleagues examined how this chain of cells changed with age, they found that the density of V-SVZ brain stem cells declined with age and in both sexes. However, these brain stem cells became more disorganized with age in males but not females. There were also sex-specific migratory patterns of brain stem cells. In young animals, brain stem cells are pretty close to the nearest vessel surface. With advanced age, male brain blood vessels get closer to the vessel surface, while in females, neuroblasts move further away.

How this situation arises is not clear but could be related to the dramatic changes Zhao and colleagues observed in the blood vessel structure. By old age, male mice have increased vessel density and increased vessel tortuosity, so normal neuroblast guidance and migration might be disrupted, leading to the V-SVZ brain stem cells being trapped close to the vasculature. In contrast, in old female mice, the vessels have become less dense, of larger diameter, and less tortuous, so there may be fewer vessels near existing chains and migration of V-SVZ stem cells away from the vessels might be facilitated.

Overall, these experiments indicate that brain stem cells and their lineage progeny are more vulnerable to aging in males than in females. “We have discovered complex age-related changes in the niche that are sex-dependent,” said Zhao and colleagues. “Most notably, male mice showed a more dramatic, detrimental response to aging in the niche, with V-SVZ blood vessels becoming narrower, more tortuous, and dense, along with greater loss of [brain blood vessels] and greater impairment of progenitor proliferation and migration than observed in females.

A Sex-Specific Chain of Being

In this study, Zhao and colleagues provide novel information regarding the complex, sex-dependent changes in the V-SVZ niche with age. This study shows that aging affects both the vascular niche and resident brain stem cells differently in males and females, underscoring the importance of addressing the interaction of biological variables, such as sex and age in studies of stem cell regulation. It will be worthwhile exploring whether these changes could contribute to different courses of treatment in age-related brain diseases in men and women.

References:

Zhao X, Wang Y, Wait E, et al. 3D image analysis of the complete ventricular-subventricular zone stem cell niche reveals significant vasculature changes and progenitor deficits in males versus females with aging [published online ahead of print, 2021 Mar 30]. Stem Cell Reports. 2021;S2213-6711(21)00142-9. doi:10.1016/j.stemcr.2021.03.012