Aging Brains Respond Differently in Males and Females, Mouse Study Reveals

A single experimental drug that sharpens memory in aging male mice does almost nothing for females, according to a new study that exposes how profoundly biological sex shapes the aging brain. Working with a strain of mice that ages at an accelerated pace, researchers found that males and females arrive at the same cognitive deficits through strikingly different cellular routes—and that a therapy capable of rescuing one sex leaves the other largely untouched. The findings, published in Aging Cell, add urgent weight to a growing movement in neuroscience: the insistence that sex must be treated as a fundamental biological variable, not an afterthought, in the search for treatments against age-related cognitive decline.

The team turned to the SAMP8 mouse, a well-established model of accelerated aging that develops learning and memory deficits as early as four months of age and, from six months onward, begins to display neuropathological hallmarks reminiscent of Alzheimer’s disease. Within the hippocampus—the brain’s memory hub—these mice undergo a characteristic sequence: an early burst of neurogenic activity in the dentate gyrus, the region where new neurons are born, followed by depletion of the resident neural stem cell pool. That exhaustion, driven by signals within the local neurogenic niche, makes the SAMP8 an ideal testing ground for interventions meant to preserve or restore the birth of new neurons in adulthood.

The compound under scrutiny, known as ER272 or DPB, is a 12-deoxyphorbol diterpene originally isolated from plants of the Euphorbia genus. Unlike some of its chemical relatives, it does not promote tumors; instead, it activates classical protein kinase C isoforms by binding their C1B regulatory domain. Previous work had shown that ER272 triggers the release of TGF-α and exerts both neurogenic and neuroprotective effects, and that a two-month treatment ameliorated cognitive decline in six-month-old male SAMP8 mice. What remained unknown was whether females would respond at all—a question that matters, because most preclinical studies of hippocampal neurogenesis have been conducted in males alone, or in mixed cohorts never analyzed by sex.

To find out, the researchers gave four-month-old male and female SAMP8 mice daily intranasal doses of ER272 for eight consecutive weeks, delivering 18 microliters of a one-micromolar solution in alternating aliquots to each nostril. Age-matched SAMR1 mice, a strain that ages normally, served as controls. Throughout the treatment period, every animal received injections of BrdU, a synthetic nucleoside that incorporates into the DNA of dividing cells, allowing the team to tag and later count every neuron and glial cell born during the experiment. Behavioral testing—open field, new object discrimination, and the Morris water maze—took place during the final two weeks, with investigators blinded to treatment assignment.

The behavioral results were unambiguous. Both male and female SAMP8 mice showed impaired spatial learning in the water maze and severely compromised episodic memory in the new object discrimination task, particularly on the “what” and “when” components that test whether an animal remembers which object it saw and when. Yet only the males benefited from the drug. Treated males spent significantly more time in the target quadrant during the water maze retention probe and fully recovered their episodic memory performance. Treated females showed only a slight, statistically insignificant improvement, and direct comparisons confirmed that ER272-treated females performed significantly worse than treated males on the “what” and “when” paradigms. Open field testing ruled out changes in general locomotor activity as an explanation.

Underlying those divergent behavioral outcomes lay equally divergent cellular pictures. In male SAMP8 mice, the number of BrdU-labeled proliferating cells in the dentate gyrus dropped, and the population of newly generated immature neurons—cells positive for both BrdU and doublecortin—fell significantly, a loss that ER272 treatment fully prevented. In treated males, BrdU-positive cell counts even exceeded those of normal-aging controls and reached roughly double the levels seen in treated females. Female SAMP8 mice, by contrast, showed no significant reduction in newly generated immature neurons compared with female controls, and the drug produced only a modest, non-significant uptick. Notably, the proportion of dividing cells that adopted a neuronal fate stayed constant across groups, suggesting the drug acts on the size of the proliferative pool rather than on cell fate decisions themselves.

Three-dimensional reconstructions of individual immature neurons deepened the contrast. In male SAMP8 mice, the dendritic trees of doublecortin-positive cells were stunted: total dendritic length, dendritic surface area, segment counts, and terminal branch numbers were all reduced relative to controls, and Sholl analysis revealed fewer intersections at 60 to 70 micrometers from the cell body. ER272 reversed every one of these morphological deficits in males. Female SAMP8 mice displayed none of these abnormalities to begin with, and the treatment had no measurable effect on their neuronal architecture. In parallel, the team documented a four-fold surge in newly generated astrocytes—S100β-positive cells born during the treatment window—in male SAMP8 mice, reflecting the age-related shift of neural stem cells toward glial rather than neuronal commitment. The drug blocked that surge in males; females, whose astrocyte numbers were roughly half those of males throughout, showed no such shift and no drug response.

Analysis of the stem cell reservoir itself completed the picture. Both sexes of SAMP8 mice carried a reduced pool of radial glia-like neural stem cells, marked by GFAP and SOX2 expression. But when the researchers used MCM2, a component of the DNA replication licensing machinery, to identify stem cells that had re-entered the cell cycle, a sex split emerged: male SAMP8 mice showed a doubled proportion of activated stem cells, which treatment pushed to three times control levels, while females showed no change. The authors suggest that males may retain a larger reserve of resting, non-dormant stem cells capable of re-entering the cell cycle when stimulated, whereas females may simply have less baseline neurogenic activity to modulate—or may be at a different stage of pathological progression at six months of age.

Perhaps the most consequential finding concerns how the data are aggregated. When the researchers pooled males and females, the combined results closely mirrored the male phenotype across nearly every measure—new neurons, mature neurons, astrocytes, stem cell activation, and cognition—effectively erasing the female-specific patterns entirely. This male-driven bias in mixed-sex analyses has been documented in other preclinical fields, but seeing it play out across an entire neurogenic aging study is a stark demonstration of why the practice persists as a blind spot. Had the team analyzed only combined cohorts, the female data would have been invisible, and the conclusion would have been that the drug works uniformly.

The authors caution that several questions remain open. The estrous cycle was not monitored, though the two-month treatment spanned multiple cycles, making transient hormonal fluctuations an unlikely driver of the directional differences observed. Biodistribution of intranasally delivered ER272 was not directly tracked, so whether the compound acts directly on the hippocampus or through broader central signaling remains unresolved, and pulse-chase designs will be needed to separate effects on proliferation, survival, and lineage progression. Sex hormones, particularly estrogens, are known to modulate stem cell proliferation and neuronal survival and may contribute to the divergent trajectories. What the study establishes firmly is that male and female brains do not simply age at different speeds along a single path—they appear to follow distinct neurogenic aging trajectories altogether. For a field racing to develop therapies that boost adult neurogenesis against dementia, that distinction may determine which patients a treatment can actually help.

Subject of Research: Sex differences in hippocampal neurogenesis and cognitive response to diterpene treatment in a mouse model of accelerated aging

Article Title: Sex‐Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging

Article References: Gómez‐Oliva, R., Chamorro‐Francisco, A., Atienza‐Navarro, I., Carrascal, L., Freire‐Aragón, M. D., Hernández‐Galán, R., Nunez‐Abades, P., García‐Alloza, M., & Castro, C. (2026). Sex‐Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging. Aging Cell, 25(10), Article e70663. https://doi.org/10.1111/acel.70663

Image Credits: AI Generated

DOI: 10.1111/acel.70663

Keywords: hippocampal neurogenesis, aging, SAMP8 mice, sex differences, ER272, dentate gyrus, neural stem cells, cognitive decline, astrocytes, Morris water maze, protein kinase C, Alzheimer's disease