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

The work, led by Yuanzhu Pu and Can Su, with corresponding author Haifeng Chen, builds on a long history of pharmacological interest in E. breviscapus. The herb, known in Chinese medicine as Dengzhan Xixin, has documented antioxidant, anti-apoptotic, and anti-inflammatory properties, and its principal constituents, including caffeoylquinic acids and the flavonoid scutellarin, have been examined for effects ranging from improved insulin sensitivity to vascular protection. What remained poorly understood, the authors note, was whether the plant could meaningfully counter cellular senescence itself, the progressive decline in cell function that underlies tissue deterioration, and if so, through which molecular machinery.

To answer that question, the researchers deployed a classic one-two punch of aging research models. The first was Caenorhabditis elegans, the transparent nematode worm that has served for decades as the workhorse of longevity genetics, allowing researchers to test lifespan effects with unprecedented genetic precision. The second was the senescence-accelerated mouse prone 8 strain, or SAMP8, a murine line that exhibits premature and exaggerated aging phenotypes, making it a useful bridge between short-lived invertebrates and mammalian physiology. Using both systems in parallel allowed the team to ask not only whether the herb works, but whether its mechanism is conserved across species separated by hundreds of millions of years of evolution.

In the worms, the results were striking. EBHM treatment prolonged average lifespan by a maximum of 18.68 percent, a substantial figure in a field where even single-digit extensions are considered noteworthy. Beyond mere survival, the treated nematodes showed significantly enhanced resistance to stress and improved motor function, indicating that the herb extended healthspan, the biologically active portion of life, rather than simply stretching out a period of frailty. The researchers also measured reduced levels of malondialdehyde, a marker of lipid damage caused by reactive oxygen species, alongside increased activity of the cell’s primary antioxidant enzymes: superoxide dismutase, glutathione peroxidase, and catalase.

The genetic dissection is where the study becomes particularly compelling. When the team repeated the lifespan experiments in mutant worms lacking functional copies of key longevity genes, the effect of the herb vanished entirely. Mutants in aak-2, the worm homolog of the metabolic sensor AMPK; sir-2.1, the nematode version of the sirtuin SIRT1; daf-16, the worm’s FOXO transcription factor; and cep-1, its p53 homolog, all failed to benefit from EBHM treatment. This pattern of epistasis, in which a compound’s effect disappears when a specific gene is disabled, is strong evidence that the herb acts through that pathway rather than through some unrelated mechanism. In other words, the plant’s longevity benefit appears to require the same genetic circuitry that caloric restriction and other proven lifespan interventions engage.

The molecular readouts filled in the picture. EBHM treatment increased the ratio of phosphorylated to total AMPK, indicating activation of this cellular energy sensor, and elevated levels of SIR-2.1 protein, the deacetylase that cooperates with AMPK in longevity regulation. The researchers used fluorescent reporter strains to watch the pathway in action: DAF-16::GFP, a tagged FOXO protein, migrated into the nucleus, where it can switch on antioxidant genes, and SOD-3::GFP, a reporter for a superoxide-dismutating enzyme under FOXO control, lit up in treated worms. These effects were dependent on DAF-16, confirming that the herb’s antioxidant boost flows through FOXO-mediated transcription rather than a direct chemical scavenging effect alone.

The team also probed the apoptosis arm of the mechanism. In the worms, EBHM downregulated the messenger RNA levels of cep-1 and ced-3, the pro-apoptotic genes corresponding to mammalian p53 and caspase-3, while upregulating ced-9, the homolog of the anti-apoptotic gene Bcl-2. This shift suggests the herb tilts the balance away from programmed cell death, a process that becomes dysregulated in aged tissues and contributes to functional decline. The finding dovetails with the broader understanding that SIRT1, when activated, deacetylates and thereby modulates p53, damping down excessive apoptotic signaling while preserving the tumor-suppressive functions that make p53 indispensable.

The mammalian experiments translated these findings into tissue-level outcomes. In SAMP8 mice treated with EBHM, the liver and kidney, organs that accumulate senescent cells and fibrotic damage with age, showed clear improvement. The number of cells staining positive for senescence-associated beta-galactosidase, a classic marker of cellular senescence, decreased, as did collagen deposition and expression of alpha-smooth muscle actin, both indicators of fibrosis. At the molecular level, the treated mice displayed elevated p-AMPK/AMPK ratios and SIRT1 expression, along with reduced levels of acetylated FOXO3a, p53, acetylated p53, p16, and p21, the latter two being canonical senescence-effectors that arrest the cell cycle. Malondialdehyde levels fell while antioxidant enzyme activities rose, the proportion of apoptotic cells diminished, the pro-apoptotic proteins Bax and caspase-3 were downregulated, and Bcl-2 was upregulated.

Taken together, the data sketch a coherent mechanistic model. EBHM activates AMPK, which in turn boosts SIRT1. Active SIRT1 deacetylates FOXO3a, freeing the transcription factor to enter the nucleus and upregulate antioxidant defense genes, which lowers oxidative stress and the lipid damage it causes. Simultaneously, SIRT1-mediated deacetylation of p53 restrains p53-driven apoptosis, while the downstream senescence markers p16 and p21 recede. The result, in both worm and mouse, is less oxidative damage, fewer senescent cells, less fibrotic scarring, and better-preserved tissue function. The authors conclude that the herb alleviates senescence through this AMPK-SIRT1 pathway, enhancing FOXO3a-dependent antioxidant defenses and modulating p53-mediated apoptosis.

The study carries obvious appeal in a field hungry for interventions that engage conserved longevity pathways, and it fits within a growing body of work on plant polyphenols as activators of sirtuin signaling, a concept sometimes framed as xenohormesis, the idea that plants under stress produce compounds that can confer stress resistance on the animals that consume them. Yet important caveats remain. The findings derive from nematodes and a mouse strain prone to accelerated aging, and the effective doses, bioavailability, and long-term safety of EBHM preparations in humans have not been established. The herb is already used clinically in China, primarily in formulations for cardiovascular and cerebrovascular conditions, which offers a measure of human safety data, but anti-aging applications would demand rigorous clinical trials. The datasets from the current study are available from the corresponding author upon reasonable request, and the work was funded by Yunnan Provincial science and technology programs. For now, the study stands as a technically thorough demonstration that a traditional medicinal plant can engage the AMPK-SIRT1-FOXO3a/p53 axis across species, a result that should energize the search for standardized, mechanism-validated anti-aging compounds from the pharmacopoeia of traditional medicine.

Subject of Research: Anti-senescence effects and AMPK-SIRT1 mechanism of the medicinal herb Erigeron breviscapus in C. elegans and SAMP8 mice

Article Title: Erigeron breviscapus alleviates senescence via AMPK-SIRT1 signaling by modulating FOXO3a-mediated antioxidant defense and p53-dependent apoptosis

Article References: Pu, Y., Su, C., Wang, X., & Chen, H. (2026). Erigeron breviscapus alleviates senescence via AMPK-SIRT1 signaling by modulating FOXO3a-mediated antioxidant defense and p53-dependent apoptosis. Biogerontology, 27(5), Article 166. https://doi.org/10.1007/s10522-026-10511-3

Image Credits: AI Generated

DOI: 10.1007/s10522-026-10511-3

Keywords: Erigeron breviscapus, aging, cellular senescence, AMPK-SIRT1, FOXO3a, p53, apoptosis, antioxidant defense, Caenorhabditis elegans, SAMP8 mice, traditional Chinese medicine, lifespan extension