LongeCityNews Last Updated: 29 January 2026 - 10:21 AM

Every cell contains hundreds of mitochondria, the distant descendants of ancient symbiotic bacteria that still contain a remnant circular genome, the mitochondrial DNA. The most important task undertaken by mitochondria is the production of the chemical energy store molecule adenosine triphosphate (ATP). A constant supply of ATP is needed to power the functions of the cell, and mitochondria are thus essential to cell function. Mitochondrial dysfunction is a feature of aging, arising in part from damage to mitochondrial DNA, and in part due to epigenetic changes that impair the operation of mitochondria and mitochondrial quality control processes. This dysfunction is particularly impactful in tissues with high energy demands, and the brain is at the top of that list.

Today's open access paper reviews present thought on mitochondrial dysfunction as a contributing (or even central) cause of Alzheimer's disease. While the authors focus on Alzheimer's disease specifically, mitochondrial dysfunction in the aging brain is broadly relevant to all neurodegenerative conditions. If it is central in any one condition, it is probably central to all. The fastest way to assess whether or not this is the case is to run clinical trials of therapies capable of greatly restoring lost mitochondrial function and observe the results.

In the near term, mitochondrial transplantation is the approach closest to realization that could in principle achieve dramatic improvement in mitochondrial function. Mitochondrial transplantation involves the delivery of large numbers of functional mitochondria harvested from cell cultures. In the context of improving the function of the aging brain, transplanted mitochondria may need to be delivered intrathecally into the cerebrospinal fluid rather than intravenously into the bloodstream, but otherwise the approach is the same. Animal studies suggest that a sizable improvement lasting for at least months is an achievable goal in human patients. The one caveat is that mitochondrial dysfunction in the brain is not just the result of the cellular mechanisms of aging, but also results from a reduced supply of oxygen and nutrients. The cardiovascular system declines with age, and thus improvement to its function may also be needed to realize the full benefits of mitochondrial transplantation into the brain.

Aging and Alzheimer's: the critical role of mitochondrial dysfunction and synaptic alterations

Alzheimer's disease (AD) is a degenerative brain disorder that is characterized by memory loss and the accumulation of two insoluble protein clumps, i.e., amyloid beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Multiple years of research have indicated that mitochondrial respiratory complex dysfunction has long been associated with the aetiology of neurodegenerative diseases such as AD. The finding of impaired oxygen and glucose transport in the brains of AD patients is the most significant indirect evidence supporting mitochondrial participation in the disease. According to the mitochondrial cascade theory, the other clinical symptoms of AD should be considered side effects, as mitochondrial malfunction is the primary cause in the majority of instances.

Electron microscope scans of the brains of AD patients have revealed altered mitochondrial morphology, including smaller mitochondria, altered and broken cristae, accumulation of osmophilic components, lipofuscin vacuoles, and elongated connected organelles. Numerous studies have been undertaken to evaluate the relationship between alterations in mitochondria (mtDNA) and AD, which have demonstrated that mtDNA levels in the brain cells and cerebrospinal fluid of AD patients have been reduced

Oxidative phosphorylation (OXPHOS) in mitochondria, which serves as the cell's energy source, produces the majority of the adenosine triphosphate (ATP). Neurons are the most ATP-consuming cell type. The primary reason for this is the requirement to maintain the ionic gradients required for ongoing neurotransmission, electrophysiological activity, and transient synaptic plasticity. In addition to being significant sources of free radical generation, defective mitochondria can trigger apoptosis by releasing cytosolic cytochrome C (cyt). Consequently, neuronal damage could result from even a little reduction in mitochondrial function.

The pathogenesis of AD has been explained through several competing and overlapping models, including the amyloid cascade, tau-first, and mitochondrial cascade hypotheses. While the amyloid and tau models emphasize extracellular plaque and cytoskeletal pathology, respectively, accumulating evidence suggests that mitochondrial dysfunction may act as an upstream trigger influencing both Aβ aggregation and tau hyperphosphorylation.

An analysis of over 3800 older adults found that shingles vaccination is associated with lower inflammation scores, slower epigenetic and transcriptomic aging, and a lower composite biological aging score [1].

Beneficial side effects

Vaccines are developed to prevent specific diseases, such as polio, measles, hepatitis, and many others. However, recent data suggest that some adult vaccines may have unintended yet beneficial effects. For example, vaccines against herpes zoster (shingles), influenza, and pneumococcus were linked to reductions in the risk of age-related diseases, such as dementia and cardiovascular diseases [2, 3, 4].

This initial data sparked the interest of other researchers, including the authors of this study, to investigate this topic further. The study’s authors specifically focused on the shingles vaccine, which protects against a viral infection caused by the reactivation of the chickenpox virus.

The researchers used data from the nationally representative U.S. Health and Retirement Study of 3,884 adults 70 years old and up in order to address the impact of shingles vaccination (specifically an earlier version called Zostavax) on seven biological aging domains: inflammation, innate and adaptive immunity, blood flow forces (cardiovascular hemodynamics), neurodegeneration, and epigenetic and transcriptomic aging that affect gene expression.

Vaccinating against aging

Analysis of the data, after adjusting for demographic, socioeconomic, and health-related factors, showed significant associations between shingles vaccination and three of the seven biological aging domains: lower inflammation scores and slower epigenetic and transcriptomic aging.

The lower observed inflammation scores suggest reduced chronic inflammation. In the elderly, chronic inflammation, often referred to as “inflammaging,” contributes to multiple age-related conditions such as heart disease, frailty, and cognitive decline.

“By helping to reduce this background inflammation — possibly by preventing reactivation of the virus that causes shingles, the vaccine may play a role in supporting healthier aging,” said Research Associate Professor of Gerontology Jung Ki Kim, the study’s first author. “While the exact biological mechanisms remain to be understood, the potential for vaccination to reduce inflammation makes it a promising addition to broader strategies aimed at promoting resilience and slowing age-related decline.”

Beyond inflammation, gene expression and epigenetic profiles were also positively affected by vaccination. Epigenetic age acceleration was assessed using DNA methylation-based aging clocks, which are used to measure biological age, assess the rate of aging, and evaluate the risk of various health outcomes, including mortality, frailty, and chronic diseases.

Since aging affects multiple systems in the body, the researchers created a composite biological aging score by integrating information across six domains into a single measurement; the adaptive immunity domain was excluded due to unexpected results, which could have obscured meaningful effects. Shingles vaccination was associated with a lower composite biological aging score, suggesting that this vaccine affects multiple bodily systems.

Overall, “This study adds to emerging evidence that vaccines could play a role in promoting healthy aging by modulating biological systems beyond infection prevention,” said Kim.

Unexpected results

However, not all measured components showed improvements. The authors reported that, contrary to their expectations, vaccination was associated with higher adaptive immunity scores, reflecting poorer adaptive immune function. This was difficult to interpret, and the lack of additional biomarkers prevented the researchers from testing some of their hypothesized explanations. They also suggest the possibility that vaccination might simultaneously have protective and potentially adverse effects.

The lack of effect of the shingles vaccine on neurodegeneration biomarkers was also rather surprising, given previous links between shingles vaccination and reduced dementia incidence. However, the researchers believe that the biomarkers they used, which reflect long-term damage, might not capture the direct effect of the vaccination on dementia; instead, the effect might be indirect, such as through reduced inflammation, which is more dynamic.

The long-term effects

While vaccination is a one-time intervention, it may have long-term effects. An analysis of the impact of vaccination over time shows that reduced epigenetic and transcriptomic aging, as well as composite biological aging scores, are present in peopple who had recently received the vaccine and in people who had received it 4 or more years earlier. While the persistence of epigenetic and gene expression effects suggests a potential for long-term effects, those effects may diminish over time, since both DNA methylation and gene expression changes were greater in people vaccinated more recently. However, this needs further investigation.

Regarding different domains of aging, the initial three years post-vaccination were not associated with changes in other measured domains. However, three or more years after vaccination, the researchers observed an association with lower inflammation and innate immunity scores, but poorer adaptive immune function. The researchers point out that these observations might suggest that the impact of the shingles vaccine on the immune system and inflammatory responses unfolds slowly over time, thereby impacting the immune system in the long term.

Beyond preventing illnesses

“These findings indicate that shingles vaccination influences key domains linked to the aging process,” said study coauthor Eileen Crimmins, USC University Professor and AARP Professor of Gerontology. “While further research is needed to replicate and extend these findings, especially using longitudinal and experimental designs, our study adds to a growing body of work suggesting that vaccines may play a role in healthy aging strategies beyond solely preventing acute illness.”

This is promising, especially since this intervention was effective even in the older population (people studied here were over 60 when they received the vaccine), who are usually less responsive to interventions. However, it remains to be determined whether stronger effects would be observed if a younger population (in their 50s) were to receive the vaccine or if participants received a newer formulation of the shingles vaccine (Shingrix).

This study also raises a very important question of whether interventions not designed to target aging have geroprotective effects. If so, some of them, such as the shingles vaccine, might be low-cost interventions with the potential to positively influence biological aging and extend healthspan.

Literature

[1] Kim, J. K., & Crimmins, E. M. (2026). Association between shingles vaccination and slower biological aging: Evidence from a U.S. population-based cohort study. The journals of gerontology. Series A, Biological sciences and medical sciences, glag008. Advance online publication.

[2] Shah, S., Dahal, K., Thapa, S., Subedi, P., Paudel, B. S., Chand, S., Salem, A., Lammle, M., Sah, R., & Krsak, M. (2024). Herpes zoster vaccination and the risk of dementia: A systematic review and meta-analysis. Brain and behavior, 14(2), e3415.

[3] Bukhbinder, A. S., Ling, Y., Hasan, O., Jiang, X., Kim, Y., Phelps, K. N., Schmandt, R. E., Amran, A., Coburn, R., Ramesh, S., Xiao, Q., & Schulz, P. E. (2022). Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. Journal of Alzheimer’s disease : JAD, 88(3), 1061–1074.

[4] Addario, A., Célarier, T., Bongue, B., Barth, N., Gavazzi, G., & Botelho-Nevers, E. (2023). Impact of influenza, herpes zoster, and pneumococcal vaccinations on the incidence of cardiovascular events in subjects aged over 65 years: a systematic review. GeroScience, 45(6), 3419–3447.

Why is it that some people exhibit only a minimal loss of cognitive function in later life? Here researchers suggest that mechanisms relating to APOE variant are relevant. Largely researched in the context of Alzheimer's disease, but more broadly applicable to other manifestations of age-related neurodegeneration, the APOE-ε4 variant may increase disease risk by promoting greater inflammation and dysfunction in microglia, among other mechanisms. In comparison people with the APOE-ε2 exhibit a lower risk of disease. The degree to which APOE variants contribute to later life inflammation and dysfunction seems likely to impact cognitive function, but is only one of a number of influences. Lifestyle choices, such as those that impact weight and fitness, affect the burden of inflammation and are thus also likely important in determining whether cognitive function is sustained in later life.

"SuperAgers" is a term used to describe oldest-old (ages 80+) adults with episodic memory performance most closely resembling adults in their 50s to mid-60s. Apolipoprotein E (APOE)-ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), while APOE-ε2 is in comparison the protective APOE allele.

The present study aims to explore APOE-ε4 and -ε2 allele frequency in SuperAgers compared to AD dementia cases and controls in a large, harmonized multicohort dataset from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). Using harmonized clinical diagnoses and cognitive domain scores (e.g., memory, executive function, language), we classified non-Hispanic Black (NHB) and non-Hispanic White (NHW) middle-aged, old, and oldest-old adults as cases, controls, or SuperAgers, and compared APOE-ε4 and -ε2 allele frequency of SuperAgers to cases and controls.

NHW SuperAgers had significantly lower frequency of APOE-ε4 alleles and higher frequency of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. Thus we demonstrated strong evidence that APOE allele frequency relates to SuperAger status.

Link: https://doi.org/10.1002/alz.71024

By far the largest single cause of human mortality is atherosclerosis, the growth of fatty plaques that narrow and weaken blood vessels. Atherosclerosis is a universal phenomenon, occurring in every older person to some degree. Absent other causes of mortality, everyone would ultimately be killed by one of the consequences of the presence of severe atherosclerosis; reduced blood flow, heart failure, or rupture of an unstable plaque leading to heart attack or stroke. A sizable industry is focused on the development of new therapies for atherosclerosis, but no approach that can reliably regress existing plaques has yet to reach clinical development. It remains a largely irreversible condition, one that can only be slowed to some degree.

Heart disease remains the leading cause of death in the U.S. and stroke has moved up to the #4 spot. Together, heart disease and stroke accounted for more than a quarter of all deaths in the U.S. in 2023, the most recent year for which data is available. Cardiovascular diseases, including all types of heart disease and stroke, claim more lives in the U.S. each year than all forms of cancer and accidental deaths - the #2 and #3 causes of death - combined.

"The good news is that, overall, fewer people are dying from any cause, and death rates are improving as life expectancy continues to rebound after the COVID-19 pandemic. However, about half of all U.S. adults continue to have some form of cardiovascular disease. Those rates are still higher than they were before the pandemic and persistent increases in common conditions like high blood pressure, diabetes, and obesity continue to drive the risk."

These health factors not only contribute to heart disease and stroke, they also lead to other complications. Because of the interconnectivity of these conditions, for the first time this year's American Heart Association's Heart Disease and Stroke Statistics Update includes a chapter on cardiovascular-kidney-metabolic (CKM) syndrome, a health disorder made up of connections between heart disease, kidney disease, diabetes, and obesity, leading to poor health outcomes.

A review of 59 studies from 2010 to 2022 found that people who had ideal cardiovascular health as measured by Life's Essential 8 had a 74% lower risk of cardiovascular events compared with those who had poor cardiovascular health. In the United States, optimal Life's Essential 8 scores could prevent up to 40% of annual all-cause and cardiovascular disease deaths among adults. Better cardiovascular health was also associated with better brain health including younger brain age, less subclinical vascular disease, slower cognitive decline, and reduced dementia risk.

Link: https://newsroom.heart.org/news/heart-disease-stroke-deaths-down-yet-still-kill-more-in-u-s-than-any-other-cause