Fight Aging!

Astrocytes make up a sizable fraction of the supporting cells of the brain, and undertake a wide range of tasks in order to maintain function. They supply metabolites needed for neural function, maintain other aspects of brain chemistry, provide structural support, and are a component of the blood-brain barrier, among many other activities. It has been noted that astrocytes tend towards greater inflammatory behavior in the aged brain, and like all cell populations a greater number of astrocytes become senescent in later life. Behaviors change in many other ways in response to the aged environment, some adaptive and some maladaptive. It remains an interesting open question as to what degree aging can be treated by simply forcing cells to behave as though they were young; answers should hopefully emerge from continued work on partial epigenetic reprogramming of living tissue, the imposition of a youthful epigenetic pattern of gene expression on aged cells.

In today's open access paper, researchers discuss two less drastic approaches to favorably changing the behavior of astrocytes in the aging brain. In one case, a small molecule is used to induce a lesser degree of inflammatory overactivation in astrocytes, leading to improved function in brain tissue in an animal study. In the other case, a gene therapy is used to enable astrocytes to manufacture more of a secreted extracellular matrix protein that is important to the creation and function of synaptic connections between neurons; levels of this protein decline with age and in neurodegenerative conditions. Again, this intervention improves function in aged brain tissue, as assessed in an animal study.

Astrocytes in Brain Aging and Neurodegeneration: Cellular Mechanisms and Interventional Strategies

We discuss how astrocyte aging contributes to cognitive decline and highlight emerging evidence on how targeting astrocytes, both genetically and pharmacologically, may rescue cognitive decline associated with aging and neurodegenerative diseases. Astrocytes produce several molecules that control synapse formation and function, which are decreased in the aging brain and in Alzheimer's disease models. In this context, recent studies indicate that astrocytes undergo significant molecular and functional remodeling during aging. Notably, astrocyte senescence has been associated with loss of lamin-B1, nuclear alterations, impaired synaptogenic and neuritogenic capacity, altered glutamate metabolism, and mitochondrial dysfunction, all of which may contribute to reduced neuronal support and circuit integrity. In parallel, recent advances have shown that astrocyte responses during aging also include diverse reactive states that vary according to brain region, microenvironment, and disease stage. Importantly, senescence-associated and reactive features are not mutually exclusive and may coexist or interact, further contributing to synaptic dysfunction and increased vulnerability to neurodegeneration.

Recent studies have emphasized the value of astrocyte phenotype and function-oriented strategies, such as restoring astrocytic metabolic and mitochondrial competence, regulating chronic inflammation, and re-establishing proper astrocyte-synapse interactions, rather than broadly suppressing astrocyte activation/reactivity. In parallel, advances in cell-type-targeted delivery and pharmacological modulation have strengthened the translational potential of astrocyte-centered interventions. In this context, we recently demonstrated that by modulating astrocyte phenotypes, either pharmacologically or through gene therapy, we can reverse cognitive decline associated with aging and in a preclinical model of Alzheimer's disease (AD).

Histone deacetylases (HDAC) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. HDAC inhibitors (iHDAC) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. To address the role of iHADC in AD, we have used the beta-amyloid (Aβ) oligomers (AβOs) toxicity model. AβOs are soluble oligomers of the amyloid-peptide that accumulate in AD brains and are considered an important toxin that lead to synaptic loss in AD. We previously found that AβOs target murine and human astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro. Recently, we have shown that the iHDAC LASSBio-1911 mitigates the effects of AβOs on synapse loss and cognitive decline in mice. This was mainly due to its ability to modulate the astrocyte phenotype.

Astrocytes from distinct brain regions contribute to synapse formation through the secretion of various synaptogenic molecules. Among these, the extracellular matrix protein, Hevin, secreted by astrocytes, has emerged as a key player. Hevin promotes the formation of excitatory synapses by bridging pre- and postsynaptic proteins. Recent evaluation of data set from AD animal models and patients demonstrated that Hevin is downregulated in both animals and patients' brain samples. We employed adenovirus-mediated overexpression of Hevin in hippocampal astrocytes of aged and APP/PS1 transgenic mice. The use of a GFAP (glial fibrillary acidic protein) gene promoter ensured astrocyte-specific expression of the transgene. Behavioral analyses revealed that Hevin overexpression not only ameliorated cognitive, synaptic, and behavioral deficits in APP/PS1 mice, but also improved performance in aged wild-type animals.

Teeth do age, becoming more brittle and prone to fracture as the cell populations of the dental pulp become less capable of conducting the necessary maintenance processes. This has only relatively recently become a topic of interest in the dental community, and so relatively little is understood in detail of the mechanisms of tooth aging. Researchers here identify loss of NFATC1 in dental pulp cells as a driver of age-related dysfunction in the maintenance of tooth structural properties, and show that this mechanism is in large part a downstream consequence of the presence of senescent cells in that tissue. Clearance of senescent cells via senolytic therapies reduces the impact of aging on teeth.

Although tooth aging is causally linked to age-associated dental degeneration and regenerative disability, its pathogenesis remains largely unelucidated, despite extensive documentation of its phenotypic alterations. Over time, alongside senescence of the mineralized parenchyma, dental pulp undergoes irreversible changes impairing its renewal capacity. This leads to brittle teeth prone to fracture and susceptible to damage as pulpal degeneration progresses and dentinogenesis fails. These age-related issues remain unresolved due to the unknown drivers. Recognition of this problem in dentistry is relatively recent, dating back only two decades.

There is now growing consensus on the importance of developing methods to counteract tooth aging, particularly pulp aging, as a crucial strategy for tooth conservation. Combining in vivo genetic tools with tissue clearing, advanced 3D imaging, and serial histological and molecular analyses, we identified and validated loss of NFATC1 activity in dental pulp mesenchymal stromal cells (MSCs) as a driver of tooth aging. Induced loss of NFATC1 activity accelerated aging, causing premature tooth aging in young adult mice. Mechanistically, we confirmed it as the cause of age-associated pulpal degeneration and regenerative disability.

Crucially, we demonstrated that senolytics therapeutically ameliorate pulpal degeneration and restore regenerative capacity to preserve vital teeth by eliminating senescent dental pulp MSCs. Similar to reports showing that senescent skeletal stem cells create an inflammatory, degenerative environment impairing skeletal repair in aged bone, our findings demonstrate that driver-induced dental pulp MSC senescence underlies poor regenerative activity in aging teeth.

Link: https://doi.org/10.1016/j.stemcr.2026.102925

Researchers here note a mechanism that encourages the innate immune cells known as microglia to better clear amyloid-β in the aging brain. The protein PM20D1 acts in the formation of N-acylamides, and generation of the product N-oleoyl-leucine encourages microglia to more efficiently remove amyloid-β aggregates. In animal models of Alzheimer's disease based on an excessive creation of amyloid-β aggregates this improves matters. As is usually the case, it remains to be seen as to whether this will help in the human condition; so far, clearance of amyloid-β via immunotherapies has not performed well, suggesting that it doesn't play as significant a role in the condition as hoped.

There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD.

OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.

Link: https://doi.org/10.1038/s41419-026-08791-1