LongeCityNews Last Updated: 30 March 2026 - 08:47 PM

It is by now clear that alterations to the composition and activities of the gut microbiome affect function in the rest of the body, including the brain. The composition of the gut microbiome changes with age, a growth in populations that provoke chronic inflammation via metabolites or direct interaction with tissues, versus a reduction in the size of populations that generate beneficial metabolites that are required for normal tissue function. The research community has started to identify specific microbial species and specific metabolites associated with specific age-related conditions, and in some cases have already demonstrated the ability to restore lost function in animal studies via interventions that alter microbial population size or metabolite levels.

This research will continue. The most plausible near term interventions to emerge into widespread use are those involving probiotics. The existing probiotics industry will most likely develop a range of new products as the evidence for benefits in animal studies emerges, and do so well in advance of large human studies of efficacy. Another potentially important approach is the use of fecal microbiota transplantation from a young donor to an aged recipient, as this approach has been demonstrated to produce lasting restoration of a more youthful composition of the gut microbiome following one course of treatment, and significant health benefits in animal models. There are caveats, such as how to screen for species that can be problematic when introduced to an older individual, but these caveats seem unlikely to provoke a replacement of fecal microbiota transplantation initiatives with efforts to develop far more complex probiotic mixtures than can currently be manufactured - synthetic microbiomes in essence.

Gut-brain axis in health and brain disease

The gut-brain axis is a complex, bidirectional network of communication systems that integrates neural, endocrine, and immune pathways, as well as metabolic processes, to regulate homeostasis and maintain physiological and cognitive equilibrium. Central to this axis is the gut microbiota, which exerts a profound influence on brain function through microbial metabolites, including short-chain fatty acids, tryptophan metabolites, and bile acids. Disruption of this microbial balance, known as dysbiosis, has been implicated in the onset and progression of major neuropsychiatric and neurodegenerative disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD).

Probiotics, which are "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host," have shown considerable promise in improving mental health symptoms. Findings suggest that specific species within the Lactobacillus and Bifidobacterium genera exert the most significant impact on alleviating mental health symptoms, particularly those associated with anxiety and depressive disorders. Furthermore, studies suggest that probiotics may enhance cognitive function and potentially slow the progression of AD. In addition, they have been shown to reduce neuroinflammation and influence both blood-brain barrier integrity and neurotransmitter regulation in PD.

Fecal microbiota transplantation (FMT) is a clinical procedure in which fecal material from a healthy donor is introduced into a recipient to help reestablish a balanced and healthy gut microbiota. The primary goal of FMT is to directly alter the recipient's gut microbial composition, thereby conferring a health benefit. This approach has gained recognition for its effectiveness in treating recurrent Clostridium difficile infections. However, its potential applications extend to a range of other conditions, including those affecting the gut-brain axis. By restoring microbial balance in the gut, FMT may lead to improvements in both gastrointestinal and brain health.

Emerging studies have focused on the application of FMT as a potential treatment for various neurodegenerative diseases. For example, preclinical studies conducted in mouse models of PD have shown that FMT from healthy donors can lead to improvements in motor function and a reduction in neuroinflammation, suggesting a promising therapeutic avenue. Animal studies in models of AD have yielded varied results, with some showing improvements in behavioral measures and reductions in amyloid plaques and neuroinflammation following FMT. Although several clinical trials have been completed, ongoing studies continue to investigate the efficacy and safety of FMT in various neurological conditions. For example, clinical studies examining the effects of FMT in patients with PD and MS have shown improvements in both motor and non-motor symptoms.

In summary, early results for FMT are encouraging, but the variability in outcomes and the overall limited data underscore the need for more rigorous and extensive clinical trials. Further clinical trials are crucial for identifying the specific conditions and patient populations that are most likely to benefit from FMT. Likewise, the current body of data on the use of FMT for treating most neurodegenerative disorders remains limited. To definitively establish the efficacy and safety of FMT in this context, large-scale, well-controlled clinical trials are necessary.

Researchers publishing in Aging Cell have discovered that using FGF21 to upregulate the sirtuin SIRT1 delays spinal disc degeneration in a rat model.

A common cause of lower back problems

Intervertebral disc degeneration (IDD) is one of the core reasons for lower back pain in older people. This nearly ubiquitous problem is a frequent target of anti-aging interventions, and we have reported on previous work in this area, which focused on a specific, senescence-related signaling pathway.

This paper, however, takes a different approach. While it also focuses on cellular senescence, it looks into the effects of FGF21, a growth factor that declines with aging and that has been reported to fight against sarcopenia. These researchers note that it has been found to have several other benefits, including slowing thymic involution [1] and, critically for this paper, improving mitophagy [2], a maintenance process that involves the consumption of damaged mitochondria.

Rather than using naturally aged rats, these researchers used a rat model of IDD, which was induced by puncturing their vertebrae under anaesthesia. Compared to a sham-operated group, the affected rats had considerable disorganization of the nucleus pulposus (NP) tissues that are vital for disc integrity along with significant fibrosis. Senescence biomarkers, including p16 and p21, were upregulated in this group, and FGF21 was significantly downregulated.

This matched data from NP tissues derived from human donors. The more degenerated samples had increased fibrosis, reduced cellular counts, increased cellular senescence markers, and fewer of the proteoglycans that are necessary for proper function of spinal discs. While FGF21 was not found to be an independent risk factor, which the researchers suggested was due to the small sample size (n = 26), it was strongly correlated with both age and symptom severity.

The researchers then looked into administering FGF21 directly into an NP cell culture. After the cells were stressed using TBHP, a low dose of FGF21 (50 ng/mL) was found to have modest benefits for cellular senescence markers, and a higher dose (200 ng/mL) was found to have more substantial benefits, reducing p16, p21, p53, and the key senescence marker SA-β-gal. This treatment also restored natural antioxidant production and the creation of ATP, which are both reduced in these cells under TBHP stress. The researchers found similar results when exposing the cells to the inflammatory factor IL-1β.

Finding the causal links

Compared to cells treated with TBHP alone, cells that were also treated with FGF21 were found to have substantial gene upregulations in autophagic maintenance processes, including mitophagy. In both humans with IDD and their rat model, the researchers noted that such autophagic markers were diminished. A closer look at the treated NP cells found that mitochondria in the TBHP-only cells are swollen and perform minimal mitophagy, while FGF21 restores some of this capacity.

The researchers hold that this process is specifically how FGF21 fights senescence in these cells. To confirm this finding, they administered a mitophagy inhibitor, Mdivi-1, alongside TBHP and FGF21, to NP cells. As they expected, suppressing mitophagy nullified the effects of FGF21, as did knocking down the mitophagy-related gene Drp-1.

Further experiments found that the PINK1-Parkin pathway was also necessary for FGF21 to upregulate mitophagy; when either of these factors was interfered with, the effects of FGF21 on both mitophagy and senescence were severely attenuated. The researchers also discovered that the sirtuin SIRT1, which is downregulated in both human IDD and this rat model, was also upregulated by FGF21. Another series of cellular experiments found the causal pathway: in these NP cells, FGF21 upregulates SIRT1, which then engages the PINK1-Parkin pathway to stimulate mitophagy and ameliorate cellular senescence.

With these results in hand, the researchers then returned to their rat model. While FGF21 did not fully ameliorate the symptoms of IDD, it substantially improved NP tissue morphology, partially restoring proteoglycans and restoring some of the discs’ size. Knocking down SIRT1 prevented these benefits from occurring.

These results are from an induced-IDD rat model, and naturally aged rats were not tested. However, the researchers have discovered a clear causal chain that occurs in NP cells. Further work will need to be done to determine if these results apply to naturally aged organisms and to human beings.

Literature

[1] Youm, Y. H., Gliniak, C., Zhang, Y., Dlugos, T., Scherer, P. E., & Dixit, V. D. (2025). Enhanced paracrine action of FGF21 in stromal cells delays thymic aging. Nature Aging, 5(4), 576-587.

[2] Ma, Y., Liu, Z., Deng, L., Du, J., Fan, Z., Ma, T., … & Zhang, Y. (2024). FGF21 attenuates neuroinflammation following subarachnoid hemorrhage through promoting mitophagy and inhibiting the cGAS-STING pathway. Journal of Translational Medicine, 22(1), 436.

Can neurodegenerative conditions be effectively treated by only changing the behavior of cells in the brain? That is an interesting question, particularly given the sizable research focus placed on epigenetic reprogramming in recent years. On the one hand there are clearly issues that occur outside cells, such as formation of aggregates or chemical changes in the extracellular matrix. There are other issues inside cells that no amount of altered cell behavior can fix, such as mutational damage to nuclear DNA. On the other hand, a variety of approaches that focus on altering epigenetic control of nuclear DNA structure and gene expression have led to improved function in animal models of neurodegenerative conditions, such as the example shown here.

Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of neurodegenerative diseases. Unlike irreversible genetic mutations, epigenetic marks such as histone methylation are dynamic and potentially reversible, making them attractive therapeutic targets. In particular, two histone methyltransferases (HMTs), GLP (EHMT1) and G9a (EHMT2), have attracted increasing attention due to their role in catalyzing the dimethylation of histone H3 at lysine 9 (H3K9me2), a repressive mark associated with transcriptional silencing. G9a/GLP-mediated epigenetic repression has been shown to influence critical processes such as neuronal development, synaptic plasticity, and memory consolidation.

Intriguingly, an aberrant upregulation of G9a activity has been linked to increased oxidative stress, neuroinflammation, and neuronal dysfunction, which are hallmarks of Alzheimer's disease (AD) and other neurodegenerative conditions. However, translating G9a inhibition into a viable therapeutic strategy has proven to be difficult. Most known G9a inhibitors, including BIX-01294, UNC0638, and A-366, suffer from poor selectivity, high cytotoxicity, and inadequate blood-brain barrier (BBB) permeability, which are limitations that are less critical in oncology but represent major obstacles for central nervous system (CNS) applications. Consequently, the therapeutic potential of G9a inhibition in neurodegeneration remains largely untapped.

Here, we report the discovery and characterization of FLAV-27, a brain-penetrant, subnanomolar inhibitor of G9a with exceptional selectivity for G9a over the closely related GLP and other methyltransferases. Unlike previously reported G9a inhibitors, FLAV-27 exhibits favorable CNS drug-like properties, including excellent BBB permeability and a strong safety profile. FLAV-27 reduces amyloid beta (Aβ) and phosphorylated tau aggregation and restores neuritic complexity in vitro. In Caenorhabditis elegans, it improves mobility, lifespan, and mitochondrial respiration. In mouse models of both late-onset AD (SAMP8) and early-onset AD (5xFAD), FLAV-27 rescues memory performance, social behavior, and synaptic structure.

Link: https://doi.org/10.1016/j.ymthe.2025.12.038

Here, researchers review what is known of the aging of heart muscle, and what might be done about it. The heart is more vital to life than any other specific muscle tissue, and thus the panoply of late life dysfunctions and other manifestations of aging are well studied in this organ. Connecting the underlying mechanisms of aging to observed changes in function remains a work in progress, and will likely only advance significantly as therapies to address specific mechanisms of aging are developed and deployed. Consider the accelerated pace at which the understanding of cellular senescence in aging has advanced since the the first senolytic drugs were demonstrated in animal studies fifteen years ago, for example.

The heart, a vital organ, works without interruption and constantly adjusts to the ever-changing demands on our body. It adapts to physiological and pathological changes, including exercise and emotional state, as well as metabolic, respiratory, and vascular abnormalities. The pumping action of the heart is determined by the health of the myocardium, which undergoes changes with ageing that are both under-investigated and incompletely understood, potentially impacting our approach to pathological conditions. Here, the alterations in cellular, tissue, and gross physiological function of the heart with age are discussed.

At the molecular level, non-coding RNAs influence cellular senescence, and extracellular vesicles induce fibrosis through matrix remodelling. Mitochondrial dysfunction and altered fatty acid oxidation reduce cellular energetics, whilst accumulation of reactive oxygen species and steatosis, as well as telomere shortening coupled with reduced autophagy, limit the myocardium's regenerative capability. Loss of cardiomyocytes, combined with senescence, requires compensatory hypertrophy, inducing myocardial stiffness and altered muscle function. In addition to these direct alterations in myocardial characteristics with ageing, other factors that can affect the myocardium indirectly are addressed, including valve calcification, resulting in regurgitation and/or stenosis; vascular abnormalities, reducing compliance and exacerbating hypertension; fibrosis leading to cardiac arrhythmias; and autonomic dysregulation, reducing cardiac adaptability.

Finally, potential modulation of cardiac ageing is discussed whilst also addressing which senescent modifications should be considered as ageing-related physiological changes of the myocardium. A better understanding of myocardial ageing will differentiate physiological changes from early, preventable, and reversible pathological changes, consequently helping to optimize management of individuals with or at risk of myocardial disease by taking into account diverse trajectories of myocardial ageing.

Link: https://doi.org/10.1093/eurheartj/ehag095