LongeCityNews Last Updated: 07 November 2025 - 08:06 AM

A growing body of literature is associated with the debate over whether persistent viral infection provides a significant contribution to Alzheimer's disease and other neurodegenerative conditions. Some viruses, such as varieties of herpes simplex virus (HSV), cannot be effectively cleared by the immune system. They linger in the body to continually provoke immune reactions. The contribution of viral infection is clearly not reliable and sizable, however, as the epidemiological evidence is mixed. Some study populations show a correlation between infection status or use of antiviral therapies, while some do not. Some researchers have proposed that significant contributions to neurodegenerative disease require the interacting presence of several viral infections, which if true would explain why studies assessing infection status for a single virus produce mixed results.

If looking at only biological mechanisms, such as HSV-1 driving greater accumulation of amyloid-β in the aging brain, or the disruptions to immune function generated by cytomegalovirus, it all sounds quite compelling. But at the end of the day, researchers have be to able to demonstrate a robust association in epidemiological data for the viral contribution to Alzheimer's disease and other neurodegenerative conditions to be taken seriously. At the moment researchers are still in search of that robust correlation, and as a consequence this remains an exploratory part of the field.

HSV-1 as a Potential Driver of Alzheimer's Disease

Globally, approximately 4 billion people, or 64% of the population under the age of 50, are infected with herpes simplex virus type 1 (HSV-1). Antiviral medications such as acyclovir, famciclovir, and valacyclovir are prescribed to symptomatic patients. A complete cure for HSV-1 remains elusive in 2025, as these medicines do not eliminate the virus. After an initial infection, HSV-1 often enters a latent state, which can be reactivated, causing recurrent outbreaks, symptomatic or asymptomatic. Emerging evidence suggests that HSV-1 may contribute to neurodegeneration, particularly in Alzheimer's disease (AD), potentially through mechanisms such as chronic neuroinflammation, amyloid-beta (Aβ) and hyperphosphorylated Tau accumulation, oxidative stress, and synaptic dysfunction. Moreover, HSV-1 proteins have been detected in the hippocampus and thalamus, both of which are affected in AD. However, the role of HSV-1 in dementia remains unclear.

In this review, we examine current evidence on the potential role of HSV-1 in the pathogenesis of dementia and consider whether targeting HSV-1 could be a viable strategy for preventing progressive neurodegeneration. Although many studies have demonstrated an association between HSV-1 and AD, further exploration is needed to determine whether HSV-1 infection is a cause or a consequence of AD degeneration. Because HSV-1 is latent in the trigeminal ganglion and travels to the brain during reactivation, an animal model that can physiologically mimic human-brain conditions remains a challenge. Thus, future studies should examine possible experimental models in order to determine the causality between HSV-1 and AD.

AD is characterized by progressive memory impairment, executive dysfunction, and visuospatial impairment. Several studies have shown that neurotropic viral infections serve as a risk factor for AD onset and progression. Regarding the contribution of HSV-1 infection to AD onset, the studies started with the observation demonstrating the association between HSV-1 DNA and amyloid plaques. 72% of HSV-1 DNA was associated with plaques, whereas only 24% of HSV-1 DNA was associated with plaques in normal brains. Furthermore, HSV-1 DNA and proteins were found in the central nervous system, particularly in the hippocampus and thalamus, which are predominantly affected in AD, supporting the association between HSV-1 infection and AD.

In an epidemiological study, a meta-analysis revealed a positive correlation between anti-HSV-1 acyclovir treatment and the potential reduction in the risk of AD development or slowing down the progression of AD symptoms. However, the analysis may be limited by the lack of data from prospective randomized controlled clinical trials. A Phase II randomized, double-blind, placebo-controlled trial of valacyclovir in patients with mild AD and evidence of HSV-1/2 infection was recently completed (NCT03282916). After 78 weeks of treatment, valacyclovir did not slow disease progression. However, it remains unclear whether a longer treatment duration or intervention at an earlier disease stage might be required to observe therapeutic effects.

Overall, the mechanisms underlying HSV-1 in regulating AD progression are unclear, and further experimental studies are needed to confirm the epidemiological association between HSV-1 and AD. In addition, it remains unclear whether the increased presence of HSV-1 DNA and proteins in brain regions is a consequence of AD-associated immune dysfunction, making the brain more susceptible to infection.

A review in Aging Cell has cataloged the harmful effects of EDA2R, a protein that affects three distinct inflammation-related pathways.

A necessary protein gone bad

Like nearly every other protein with documented harmful effects, this one is required for certain systems to function properly. The EDA gene is needed for proper skin development [1] and hair follicle creation [2], and animals with mutated forms of this gene suffer from ectodermal dysplasia, which causes severe malformations in these areas [3].

However, this gene is a member of the tumor necrosis factor (TNF) superfamily [4], which provides a hint as to its potential undesirable effects; TNF-α is a well-known inflammatory biomarker. As previous work has linked EDA2R to muscle atrophy in cancer [5] and some evidence has already suggested that it may be a biomarker of aging [6], these reviewers have gone through the literature to determine what this gene and its protein are doing.

Beyond the skin

As expected, initial work on EDA2R has found that this gene is expressed in the hair and skin [7]. Further work found that it is expressed in the fat, vasculature, and immune system [8], and a comprehensive tissue expression database found that it is highly expressed in the reproductive and endocrine systems along with many other organs. This gene is located close to androgen-related genes on the X chromosome, so it is unsurprising that it has related effects involving male pattern baldness [9] and that its tissue expression varies between men and women [10]; that particular study also pinpointed EDA2R as a potential biomarker of aging. Furthermore, and perhaps more crucially, its genetic locus has been found to be associated with lipid and lipoprotein metabolism [11].

There are three different pathways by which EDA2R appears to lead to inflammaging. Through TRAF6, the well-known canonical NF-κB pathway and the JNK pathway can be activated, but a different ligand, TRAF3, activates the non-canonical NF-κB pathway. All three of these pathways have been documented to be involved in inflammation [12-14].

There have been several studies suggesting a direct relationship between EDA2R and both inflammatory and age-related diseases. Overexpression of EDA2R is associated with an overexpression of lipids related to acne [15], and it is increased in progeria as well [10]. Another study found that its overexpression is related to many other lipid-related disorders, including characteristics of obesity along with metabolic issues; that study also found a related increase in inflammation [16]. There has also been a documented, significant relationship between EDA2R and frailty [17].

The researchers sum up these findings: “Collectively, the evidence from diverse cohorts, animal models and clinical studies underscores EDA2R gene expression as a robust and versatile biomarker of multiple interconnected pathophysiological processes.”

Further work appears to agree with this assessment. One study that used UK Biobank data found that the EDA2R protein is associated with premature aging, including both frailty and multiple epigenetic aging clocks, such as PhenoAge, along with having a negative healthspan association [18]. A different study found it to be associated with a broad range of cancers [19], another study found it to be linked to metabolic disorders such as diabetes [20], and yet another found a link between EDA2R and dementia [21].

A potentially difficult target

The reviewers took some time to discuss the physical intricacies of EDA2R as a protein, including its shape and the protein it binds to. They note its similarities to EDAR and that there are only two amino acid residues that distinguish the two, which may make it more difficult to develop a drug that targets EDA2R without affecting EDAR. The protein’s folded structure has also not been conclusively determined, although AI-based systems such as AlphaFold have made good guesses and it is possible to use expensive but slow microscopy techniques to have a definitive answer.

However, there are some existing techniques that appear to decrease EDA2R. A mouse study found that ginkgolide B decreases the expression of the gene’s murine counterpart [22], while human studies have found that excessive bed rest increases it [23] while fasting decreases it [24]. This suggests that it may be modulated by the same general treatment recommended everywhere: diet and exercise.

Literature

[1] Mikkola, M. L. (2008). TNF superfamily in skin appendage development. Cytokine & growth factor reviews, 19(3-4), 219-230.

[2] Lee, J., & Tumbar, T. (2012, October). Hairy tale of signaling in hair follicle development and cycling. In Seminars in cell & developmental biology (Vol. 23, No. 8, pp. 906-916). Academic Press.

[3] Katthika, V. K., & Auerkari, E. I. (2018, May). Ectodermal Dysplasia. In 11th International Dentistry Scientific Meeting (IDSM 2017) (pp. 230-238). Atlantis Press.

[4] Dostert, C., Grusdat, M., Letellier, E., & Brenner, D. (2019). The TNF family of ligands and receptors: communication modules in the immune system and beyond. Physiological reviews, 99(1), 115-160.

[5] Bilgic, S. N., Domaniku, A., Toledo, B., Agca, S., Weber, B. Z., Arabaci, D. H., … & Kir, S. (2023). EDA2R–NIK signalling promotes muscle atrophy linked to cancer cachexia. Nature, 617(7962), 827-834.

[6] Arif, M., Lehoczki, A., Haskó, G., Lohoff, F. W., Ungvari, Z., & Pacher, P. (2025). Global and tissue-specific transcriptomic dysregulation in human aging: Pathways and predictive biomarkers. GeroScience, 1-20.

[7] Bergqvist, C., Ramia, P., Abbas, O., & Kurban, M. (2017). Genetics of syndromic and non‐syndromic hereditary nail disorders. Clinical Genetics, 91(6), 813-823.

[8] Kanoni, S., Graham, S. E., Wang, Y., Surakka, I., Ramdas, S., Zhu, X., … & Leonard, H. L. (2022). Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. Genome biology, 23(1), 268.

[9] Prodi, D. A., Pirastu, N., Maninchedda, G., Sassu, A., Picciau, A., Palmas, M. A., … & Pirastu, M. (2008). EDA2R is associated with androgenetic alopecia. Journal of Investigative Dermatology, 128(9), 2268-2270.

[10] Barbera, M. C., Guarrera, L., Re Cecconi, A. D., Cassanmagnago, G. A., Vallerga, A., Lunardi, M., … & Bolis, M. (2025). Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses. Nature Communications, 16(1), 1898.

[11] Zoodsma, M., Beuchel, C., Yasmeen, S., Kohleick, L., Nepal, A., Koprulu, M., … & Langenberg, C. (2025). A genetic map of human metabolism across the allele frequency spectrum. Nature Genetics, 1-11.

[12] Moneva-Sakelarieva, M., Kobakova, Y., Konstantinov, S., Momekov, G., Ivanova, S., Atanasova, V., … & Atanasov, P. (2025). The role of the transcription factor NF-kB in the pathogenesis of inflammation and carcinogenesis. Modulation capabilities. Pharmacia, 72, 1-13.

[13] Wu, N., Wang, S., Zhang, Y., & Wang, S. (2025). Research Progress on Anti-Inflammatory Mechanism of Inula cappa. International Journal of Molecular Sciences, 26(5), 1911.

[14] Kaltschmidt, C., Greiner, J. F., & Kaltschmidt, B. (2021). The transcription factor NF-κB in stem cells and development. Cells, 10(8), 2042.

[15] Kwack, M. H., Hamida, O. B., Lee, W. J., & Kim, M. K. (2024). EDA-A2 increases lipid production in EDA2R-expressing human sebocytes. Journal of Dermatological Science, 113(1), 34-37.

[16] Arif, M., Lehoczki, A., Haskó, G., Lohoff, F. W., Ungvari, Z., & Pacher, P. (2025). Global and tissue-specific transcriptomic dysregulation in human aging: Pathways and predictive biomarkers. GeroScience, 1-20.

[17[ Perez, K., Ciotlos, S., McGirr, J., Limbad, C., Doi, R., Nederveen, J. P., … & Melov, S. (2022). Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence. Aging (Albany NY), 14(23), 9393.

[18] Ma, L. Z., Liu, W. S., He, Y., Zhang, Y., You, J., Feng, J. F., … & Yu, J. T. (2025). Plasma proteomics identify novel biomarkers and dynamic patterns of biological aging. Journal of Advanced Research.

[19] Papier, K., Atkins, J. R., Tong, T. Y., Gaitskell, K., Desai, T., Ogamba, C. F., … & Travis, R. C. (2024). Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank. Nature Communications, 15(1), 4010.

[20] Qian, H., Wu, C., Li, B., Rosenzweig, A., & Wang, M. (2025). Plasma Proteomics Linking Primary and Secondary diseases: Insights into Molecular Mediation from UK Biobank Data. medRxiv, 2025-08.

[21] Gong, J., Williams, D. M., Scholes, S., Assaad, S., Bu, F., Hayat, S., … & Steptoe, A. (2025). Unraveling the role of proteins in dementia: insights from two UK cohorts with causal evidence. Brain Communications, 7(2), fcaf097.

[22] Lee, C. W., Wang, B. Y. H., Wong, S. H., Chen, Y. F., Cao, Q., Hsiao, A. W. T., … & Lee, O. K. S. (2025). Ginkgolide B increases healthspan and lifespan of female mice. Nature aging, 5(2), 237-258.

[23] Fernandez‐Gonzalo, R., Tesch, P. A., Lundberg, T. R., Alkner, B. A., Rullman, E., & Gustafsson, T. (2020). Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures. The FASEB Journal, 34(6), 7958-7969.

[24] Pietzner, M., Uluvar, B., Kolnes, K. J., Jeppesen, P. B., Frivold, S. V., Skattebo, Ø., … & Langenberg, C. (2024). Systemic proteome adaptions to 7-day complete caloric restriction in humans. Nature metabolism, 6(4), 764-777.

Sirtuins are involved in the regulation of metabolism in various ways, and are clearly quite important to cell function as their structure is very similar in species as divergent as yeast, flies, and humans. Sirtuin 1 as a target for interventions in aging was intensely overhyped and likely not actually very useful in a practical sense. Sirtuin 3 is more interesting, based on research suggesting that it could have calorie restriction mimetic effects, and is involved in mitochondrial function, well known to have a role in aging. Sirtuin 6 is also interesting, as it slows aging in mice, but the mechanisms involved are less well understood. A company is presently working on gene therapies based on sirtuin 6 upregulation. Here, researchers report on their production of profile of these sirtuins in a small population of people at various ages, which might be of interest in the context of growing efforts to modestly slow aging by targeting sirtuins 3 and 6.

While modulation of SIRT1, SIRT3 and SIRT6 extends lifespan in model organisms, evidence in extreme-age humans is scarce. We quantified protein and mRNA levels, and protein-to-mRNA ratios for SIRT1, SIRT3 and SIRT6 in buccal epithelial cells obtained from healthy young adults, middle/late-aged individuals and nonagenarians/centenarians residing in a longevity-enriched region of south-eastern Azerbaijan. The cohort comprised 23 participants, stratified by sex and cardiovascular disease (CVD) status (5 per sex/CVD subgroup).

Our study has shown that although SIRT1, SIRT3 and SIRT6 levels predictably fell with age, the magnitude of these declines was significantly influenced by both sex and baseline cardiovascular health. Women retained higher absolute pools of SIRT1 and SIRT3 and exhibited a smaller loss of SIRT6 than men; their protein-to-mRNA ratios - our proxy for translational efficiency - rose by ≈30% for SIRT3 and SIRT6, whereas the male increase was modest. This pattern is consistent with hormone-dependent regulation: estrogens acting through estrogen receptor (ER)-α/β up-regulate SIRT1 transcription in endothelial and cardiac cells, via the estradiol-ERα interaction boost SIRT3 expression and mitochondrial targeting, enhancing oxidative phosphorylation, antioxidant defenses, and mitophagy for improved mitochondrial health and enhance SIRT6 activity by shielding critical acetyl-lysine residues, whereas androgens are neutral or even suppressive.

Our findings likewise showed that the presence of cardiovascular disease (CVD) reshapes the sirtuin axis far more dramatically than chronological aging and sex. We observed a decline in SIRT1, SIRT3, and SIRT6 levels, broadly consistent with a ~50% reduction in SIRT1 reported in ischemic heart disease cohorts and a ~35% decline in SIRT3 under pressure-overload conditions. In contrast, SIRT6 behaves differently: although its absolute protein level fell by ~73%, the protein-to-mRNA ratio remained virtually unchanged This pattern exemplifies translational buffering whereby cells upregulate translation of selected proteins to maintain critical functions despite drops in mRNA levels. This is more accurately framed as an emergency protective buffer, rather than a pathological driver.

This pilot study is the first to profile SIRT1, SIRT3 and SIRT6 across sex, age and cardiovascular health, defining a unified "sirtuin phenotype" that integrates nuclear energy sensing, mitochondrial integrity and chromatin maintenance as axes of cellular resilience. Although based on a small, cross-sectional cohort, the large and internally consistent effect sizes pave the way for longitudinal studies to validate sirtuin translational efficiency as a predictive biomarker of healthy ageing and cardiovascular resilience across sexes and as a target for sirtuin-modulating interventions aimed at extending healthspan.

Link: https://doi.org/10.3390/biology14101353

Here find a review of what is known of the ways in which age-related changes in the gut microbiome can contribute to the chronic inflammation of aging and development of neurodegenerative conditions. The ability to accurately map the composition of the gut microbiome by sequencing microbial DNA, in particular species-specific variations in the 16S rRNA gene, has produced a vast and growing body of data. Researchers have linked specific microbial populations to specific age-related conditions, and shown that the balance of populations shifts with age to favor those that provoke the immune system at the expense of those producing beneficial metabolites. This is the first step on the road to creating interventions capable of the lasting restoration of a more youthful gut microbiome, a goal that we know is possible because it can be achieved via fecal microbiota transplantation from a young donor to an old recipient, and approach that improves health and slows aging in animal studies.

Neurodegenerative diseases (NDs) represent a major global health challenge in aging populations, with their incidence continuing to rise worldwide. Although substantial progress has been made in elucidating the clinical features and molecular underpinnings of these disorders, the precise mechanisms driving neurodegeneration remain incompletely understood. This review examines the increasing significance of the gut-brain-immune triad in the pathogenesis of NDs, with particular attention to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It explores how disruptions in gut microbiota composition and function influence neuroinflammation, blood-brain barrier integrity, and immune modulation through microbial-derived metabolites, including short-chain fatty acids, lipopolysaccharides, and bacterial amyloids.

In both Alzheimer's and Parkinson's diseases, a reduced abundance of short-chain fatty acid-producing bacterial taxa has been consistently associated with heightened pro-inflammatory signaling, thereby facilitating disease progression. Although detailed mechanistic understanding remains limited, experimental evidence - primarily from rodent models - indicates that microbial metabolites derived from a dysbiotic gut may initiate or aggravate central nervous system dysfunctions, such as neuroinflammation, synaptic dysregulation, neuronal degeneration, and disruptions in neurotransmitter signaling via vagal, humoral, and immune-mediated pathways.

The review further highlights how gut microbiota alterations in amyotrophic lateral sclerosis and multiple sclerosis contribute to dysregulated T cell polarization, glial cell activation, and central nervous system inflammation, implicating microbial factors in disease pathophysiology. A major limitation in the field remains the difficulty of establishing causality, as clinical manifestations often arise after extended preclinical phases - lasting years or decades - during which aging, dietary patterns, pharmacological exposures, environmental factors, and comorbidities collectively modulate the gut microbiome. Finally, the review discusses how microbial influences on host epigenetic regulation may offer innovative avenues for modulating neuroimmune dynamics, underscoring the therapeutic potential of targeted microbiome-based interventions in neurodegenerative diseases.

Link: http://dx.doi.org/10.14218/JTG.2025.00027