Fight Aging!

In today's open access paper, researchers argue that the regeneration of outer, visible ear tissue is a useful area of focus for understanding why mammals are limited in their regenerative capacity. Species such as salamanders and zebrafish can regenerate limbs and internal organs, and researchers would like to understand how to enable this capability in mammals. The ear is interesting in this respect because some mammals are capable of regeneration of ear tissue, while others are not, giving a starting point for a closer comparison of the relevant biochemistry between more similar species. Mice are incapable of ear tissue regeneration, which is why ear notching is a common means of animal identification used in laboratories. Interestingly, this is how the exceptional regenerative capacity of MRL mice was discovered - the ear notches healed.

This leads to the advance noted today, in which researchers identified mechanisms that allow some mammals to regenerate ear tissue. They succeeded in reproducing this outcome in mice via upregulation of ALDH1A2 and consequent changes in fibroblast behavior in injured tissues. In most mammals, scarring forms in place of complete regeneration of lost tissue following injury. Fibroblasts are the cells responsible for depositing the extracellular matrix that forms scar tissue. Other lines of work have pointed to differences in the behavior of macrophages and senescent cells in species with different regenerative capacities, and all of these cell populations interact in complex ways following injury and during regeneration. A complete picture remains to be established, but this ALDH1A2 overexpression research has practical implications for human regenerative medicine; there may be a basis for forms of therapy here.

Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch

Regeneration is well maintained in some animal lineages but has been lost in many others during evolution and speciation. Identification of the causal mechanism underlying the failure of regeneration in mammals through comparative strategies is usually entangled by the large phylogenetic distance from highly regenerative species (mostly lower vertebrates). Exploration of principles in the evolution of regeneration demands an organ with easy accessibility and diverse regenerative capacities. One such mammalian organ is the ear pinna, which evolved to funnel sound from the surrounding environment for better distinguishing between ambient noise and predators or prey. The ear pinna possesses complex tissues such as skin and cartilage and exhibits remarkable diversity in the ability to regenerate full-thickness holes punched through this organ in placental mammals.

By performing a side-by-side comparison between regenerative species (rabbits, goats, and African spiny mice) and nonregenerative species (mice and rats), we found that the failure of regeneration in mice and rats was not due to the breakdown of tissue-loss triggered blastema formation and proliferation. Single-cell RNA sequencing and spatial transcriptomic analyses of rabbits and mice identified the response of wound-induced fibroblasts (WIFs) as a key difference between the regenerating and nonregenerating ear pinna.

Gene overexpression studies discovered that Aldehyde Dehydrogenase 1 Family Member A2 (Aldh1a2), encoding a rate-limiting enzyme for the synthesis of retinoic acid (RA) from retinaldehyde, was sufficient to rescue mouse ear pinna regeneration. The activation of Aldh1a2 upon injury was correlated with the regenerative capacity of the tested species. Furthermore, we demonstrated that the deficiency of Aldh1a2 expression, together with the augmented activity of the RA degradation pathway, contributed to insufficient RA production after injury and eventually the failure of regeneration. An exogenous supplement of RA - but not the synthetic precursor retinol - was sufficient to induce regeneration by directing WIFs to form new ear pinna tissues. The inactivation of multiple Aldh1a2-linked regulatory elements accounted for the injury-dependent deficiency of Aldh1a2 in mice and rats. Importantly, activation of Aldh1a2 was sufficient to promote ear pinna regeneration in transgenic mice.

Microglia are innate immune cells of the brain, similar to macrophages elsewhere in the body. A growing body of evidence points to maladaptive inflammatory behavior of microglia in the aging brain as an important contribution to the onset and progression of neurodegenerative conditions such as Alzheimer's disease. Some microglia become inflammatory in response to the damaged environment of aged brain tissue, but others have become senescent. Senescent cells cease replication and instead turn their efforts to secreting disruptive inflammatory signals, harmful to tissue structure and function when sustained over the long term.

Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy. This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.

We employed APP/PS1 mice and naturally aged mice. Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, amyloid-β peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, p21, and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.

These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.

Link: https://doi.org/10.1186/s13195-025-01783-x

A mountain of human epidemiological data demonstrates that physical activity and fitness correlate with a reduced incidence of age-related disease, a slower age-related decline of function. Adding to that, researchers here show that cumulative physical activity over the long term correlates with slowed loss of cognitive function. While human data can only reliably produce correlations, animal studies convincingly demonstrate that exercise does in fact improve long-term health. It remains one of the most robust interventions for slowing the aging process, the bar to beat when developing novel therapies to treat aging.

Given the lack of effective pharmacological interventions for dementia patients, modifying risk factors associated with dementia has become a critical area of research. Current evidence shows that physical activity (PA) has emerged as one of the most promising protective measures against all-cause dementia, as well as Alzheimer's disease (AD), vascular dementia, and Parkinson's disease. PA has the potential to reduce dementia risks by 2%. Prior to the dementia onset, a growing body of research has consistently shown that higher levels of PA are associated with better cognitive function, a slower rate of cognitive decline, and a lower risk of cognitive impairment.

First, PA has been shown to improve cognitive reserve, the brain's ability to adapt and compensate in the face of changes due to age, pathology, or insult without developing cognitive impairment. Besides, PA improves blood flow to the brain, reduces inflammation, which improves brain function, and assists in maintaining cognitive performance. These mechanisms suggest that PA not only plays a critical role in sustaining cognitive health but may also have a preventive effect on cognitive decline throughout the aging process.

While some evidence suggests that increased PA may help delay cognitive decline, findings from a randomized clinical trial reported no significant improvement following a six-month PA intervention. To the best of our knowledge, there is still a lack of robust evidence on the association of sustained, long-term engagement in PA with cognitive decline over time for older age. Thus, this study aims to fill this gap in the literature by examining the longitudinal association between cumulative PA over time and subsequent cognitive decline in cognitively healthy adults aged 50 years and older.

This study included 13,450 cognitively healthy participants from the Health and Retirement Study, 2004-2020, with a mean follow-up duration of 11.06 years. Higher cumulative PA was associated with delayed declines in global cognition, memory, and executive function, and such protective benefits grew over the 16-year study period. Longer PA engagement was associated with progressively delayed cognitive decline. We conclude that PA engagement over long timeframes may better maintain cognitive performance.

Link: https://doi.org/10.1016/j.tjpad.2025.100194

Variants of the APOE gene (the most common labeled as APOE-ε2, APOE-ε3, and APOE-ε4) have been show to alter the risk of developing Alzheimer's disease. Work in recent years has pointed to effects on the behavior of microglia in the aging brain as the important mechanism is driving risk. Bad variants of APOE, predominantly APOE-ε4 in the population at large, lead to greater inflammation driven by activated and dysfunctional microglia. Good variants suppress that inflammation. Various lines of evidence suggest that lipid metabolism in microglia becomes disrupted with age, driving inflammatory behavior. APOE plays a number of important roles in lipid metabolism, and there are significant differences in the capabilities of the different APOE variants.

While some consensus exists in the research community regarding the high level view of the biochemistry noted above, there is much left to accomplish when it comes to fleshing out the fine details. Today's open access paper is an example of this research, aimed at better mapping the connection between APOE and inflammatory signaling. The researchers show that a rare APOE variant suppresses the cGAS-STING innate immune pathway that reacts to forms of molecular damage in the cell with inflammatory signaling. This reaction is useful in youth, but becomes maladaptive in cells in aged tissues, burdened with damage that provokes constant and excessive inflammation. That inflammation in turn drives the onset and progression of neurodegenerative conditions such as Alzheimer's disease.

Alzheimer's Protective Mutation Works by Taming Inflammation in the Brain

Alzheimer's disease has long defied scientific efforts to understand its causes and develop effective treatments. Growing evidence suggests that tau - not amyloid - is the key driver of neurodegeneration and cognitive decline. What determines an individual's susceptibility or resistance to tau toxicity remains poorly understood. The mutation APOE3-R136S - known as the "Christchurch mutation" as it was discovered in Christchurch, New Zealand - protects against tau pathology and cognitive deterioration despite extensive amyloid buildup, offers an important clue.

This rare mutation is found in the APOE gene encoding a cholesterol transport protein (apolipoprotein E). In 2019, scientists studying a Colombian family with hereditary early-onset Alzheimer's, which typically strikes by age 50, reported that one family member, who had two copies of the Christchurch mutation, remained cognitively healthy into her 70s. Despite high brain amyloid, she exhibited low levels of tau. Subsequent research, mostly in mouse models, has confirmed the Christchurch mutation's beneficial effects - but researchers still aren't sure how it exerts protection.

In the new study, researchers engineered the Christchurch mutation into the APOE gene in mice that develop tau accumulation, and found that it protected the animals from hallmark Alzheimer's features -including tau accumulation, synaptic damage, and disruptions in brain activity. These protective effects were traced to suppression of the cGAS-STING pathway, an innate immune signaling cascade normally activated in response to viral threat but is chronically activated in Alzheimer's disease.

Researchers further discovered that the protective mechanism of the Christchurch mutation can be largely attributed to taming microglia, brain-resident immune cells. These cells and their inflammatory state in Alzheimer's have long been seen as potential drivers of the disease process. When the researchers treated mice with tau pathology using a small-molecule inhibitor of cGAS-STING signaling, they observed synapse-protecting effects and molecular changes in brain cells that closely resembled those seen with the protective mutation.

The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway

The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear.

Here, we replaced mouse Apoe with wild-type human APOE3 or APOE3S/S on a tauopathy background. The R136S mutation decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in hippocampal theta and gamma power. Additionally, the R136S mutation reduced interferon responses to tau pathology in both mouse and human microglia, suppressing cGAS-STING pathway activation.

Treating E3 tauopathy mice with a cGAS inhibitor protected against tau-induced synaptic loss and induced transcriptomic alterations similar to the R136S mutation across brain cell types. Thus, suppression of the microglial cGAS-STING-interferon pathway plays a central role in mediating the protective effects of R136S against tauopathy.

The signal molecules secreted by senescent cells can encourage other nearby cells to also become senescent. Thus the high burden of lingering senescent cells in aged tissues is both directly harmful to tissue structure and function, but also indirectly harmful by encouraging further growth of that burden of cellular senescence. The research community has investigated which of the many different components of the senescence-associated secretory phenotype (SASP) are most important in producing bystander senescence. Here, researchers presents evidence for the unoxidized form of HMGB1 to be a good target for suppression of this transmission of the senescent state between cells.

Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence. We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.

Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration. Thus targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.

Link: https://doi.org/10.1016/j.metabol.2025.156259

Base editing, such as via the various CRISPR-based approaches, is a powerful technology for making small changes to DNA sequences. It only works in the nuclear genome, however. Researchers have recently demonstrated base editing that works for the hundreds of mitochondrial genomes present in a cell. This is good for patients with single detrimental inherited mitochondrial mutations, but it remains to be seen as to whether base editing can be applied usefully to the problem of stochastic DNA damage in aging. How does one repair a million different mutations in a trillion different genomes? That capability seems beyond reach at the present time. Other ways forward appear more achievable, such as replacing stem cell populations with youthful, minimally damaged cells, allowing tissues to be slowly cleared of mutational burden over time, or delivering large numbers of undamaged mitochondria that cells take up to replace the existing damaged populations.

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells.

Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity.

To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

Link: https://doi.org/10.1371/journal.pbio.3003207

Mitochondrial uncoupling is the process by which mitochondria in cells switch from producing the chemical energy store molecule adenosine triphosphate (ATP) to releasing that energy as heat. This is of interest in the context of aging because upregulation of mitochondrial uncoupling via a range of strategies appears to somewhat slow aging in animal studies. Sustained upregulation of mitochondrial uncoupling also produces a reduction in fat tissue and weight loss. Humans being humans, there is considerably more interest in that outcome than in effects on aging, particularly now that weight loss drugs have become a large revenue source for the major pharma companies.

Historically, researchers have struggled to produce mitochondrial uncoupling drugs that will not kill people through overheating if taken at a high enough dose. One of the first such drugs to be developed and fairly widely used, back in the early 20th century, was 2,4-dinitrophenol (DNP). While there is very little literature on accidental deaths as a result of its use, it is certainly possible to take enough DNP to die from hyperthermia within a few days without any immediate sign that a fatal dose was ingested, and without any recourse once realization sets in. Any drug that directly upregulates uncoupling in the same way will likely have similar characteristics.

In today's research materials, the authors claim to have found a safe approach that bypasses the mechanism used by past approaches to upregulate uncoupling, meaning to influence the activity of uncoupling protein 1 (UCP1). In this approach, UCP1 is not involved in the switch from ATP generation to thermogenesis, and further the effect only occurs in adipose cells, not body-wide. Given present biases in funding and interest, the researchers of course pitch this as a strategy for weight loss, but it could be interesting in the context of aging as well.

Article presents innovative drug for controlling weight and blood sugar

The experimental drug, currently called SANA (short for "salicylate-based nitroalkene"), is a derivative of salicylate, a chemical compound with analgesic and anti-inflammatory properties found naturally in plants and used to make drugs such as aspirin (acetylsalicylic acid). Researchers initially sought to develop an anti-inflammatory drug. To this end, they tested several chemical modifications to the salicylate molecule. "We wanted the precursor used to be as safe as possible. Salicylate is the drug that's been known the longest, and many people consume its derivatives daily. However, we observed that instead of protecting against inflammation, the molecule we synthesized protects against diet-induced obesity."

Two different models were used to test this effect in animals. In the first model, SANA was administered to mice alongside a high-fat diet, which prevented any weight gain. Meanwhile, the animals in the control group gained between 40% and 50% of their body weight over eight weeks. In the second model, treatment began after the animals were obese. After three weeks, the mice had lost 20% of their body mass. There was also a reduction in blood sugar, improved insulin sensitivity, and a decrease in fat accumulated in the liver (a condition known as hepatic steatosis for which there is still no effective pharmacological treatment).

Experiments showed that SANA specifically targets adipose tissue, activating thermogenesis through an unconventional mechanism. It can therefore be considered the first in a new class of anti-obesity drugs. It does not affect the central nervous system or digestive system or appetite. Thermogenesis is typically mediated by a protein called UCP1, which is found within mitochondria. UCP1 is activated in certain situations, such as exposure to cold. It then interferes with the synthesis of ATP (adenosine triphosphate), the cellular fuel. This causes the energy generated by cellular respiration to dissipate as heat. However, this is not the case with SANA. The new drug causes adipocytes to use creatine, a compound formed by three amino acids (arginine, glycine, and methionine), as an energy source to produce heat without involving the UCP1 protein.

According to the researchers, the observed impact on body temperature is small and does not pose a significant health risk. "Older thermogenic agents, such as dinitrophenol, have an effect on the mitochondria of the entire body, causing a large increase in temperature and overloading the cardiovascular system, which needs to increase blood pressure for blood to reach the periphery and dissipate heat. But in the case of SANA, there's only action on the mitochondria of adipose tissue."

A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss

Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity.

Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200-800 mg) in healthy lean volunteers; (B) multiple ascending doses (200-400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight, and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment.

The trends in cardiovascular disease over the past 50 years are a success story for public health and medical progress. Even as demographic aging leads to more older people suffering more age-related disease, the risk for any given individual of suffering the most severe outcomes of cardiovascular disease has fallen. Still, atherosclerotic cardiovascular disease remains the single largest cause of human mortality, and the growth of obstructive atherosclerotic plaque in arteries remains largely irreversible. For every fortunate individual who experiences some plaque regression with an aggressive combination of lifestyle change and medication, there are many more who see no benefit. As severe outcomes such as heart attack have declined in incidence, deaths now occur as a result of other consequences of atherosclerotic plaque. New approaches and better therapies are much needed.

While heart disease has been the leading cause of death in the U.S. for over a century, the past 50 years have seen a substantial decrease (66%) in overall age-adjusted heart disease death rates, including a nearly 90% drop in heart attack deaths, according to new research. During that time, there have been major shifts in the types of heart disease people are dying from, with large increases in deaths from heart failure, arrhythmias, and hypertensive heart disease.

In an analysis of data from the U.S. Centers for Disease Control and Prevention, researchers reviewed the age-adjusted rates of heart disease deaths among adults ages 25 and older from 1970 to 2022. Over this 52-year period, heart disease accounted for nearly one-third of all deaths (31%). During this time, heart disease death rates decreased substantially, from 41% of total deaths in 1970 to 24% of total deaths in 2022. In 1970, more than half of all people who died from heart disease (54%) died because of a heart attack - a type of acute ischemic heart disease. The age-adjusted death rate decreased 89% by 2022, when less than one-third of all heart disease deaths (29%) were caused by a heart attack. Conversely, during this time, the age-adjusted death rate from all other types of heart disease (including heart failure, hypertensive heart disease and arrhythmia) increased by 81%, accounting for 9% of all heart disease deaths in 1970 and 47% of all heart disease deaths in 2022.

Link: https://newsroom.heart.org/news/still-top-cause-of-death-the-types-of-heart-disease-people-are-dying-from-is-changing

Researchers have considered a role for dysregulation of insulin metabolism in the development of Alzheimer's disease, to the point of suggesting that it might be classified as a type 3 diabetes. Epidemiological data shows that Alzheimer's is nowhere near as clearly a direct, reliable consequence of obesity and consequent metabolic dysfunction as is the case for type 2 diabetes, however, indicating that the story is probably more complex. Here, researchers discuss the role of insulin resistance in Alzheimer's disease and the existing body of evidence, pro and con, relating to approaches to therapy based on insulin delivery.

The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer's disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer's disease and accelerated aging.

Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer's disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagonlike peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative stress and neuroinflammation.

This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative stress regulation, as these are pivotal in both Alzheimer's disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders.

Link: https://doi.org/10.4103/NRR.NRR-D-25-00144

Leakage of DNA fragments from either the nucleus or mitochondria into the cell cytosol is characteristic of a wide range of forms of cell stress, dysfunction, and damage. One component of the innate immune system is that all cells incorporate mechanisms to recognize the presence of inappropriately localized DNA and raise the alert via the secretion of inflammatory signals. This is in part a defense against bacterial and viral infection, but the mechanisms are sufficiently non-specific to also react to a cell's own DNA when it is mislocalized. This is an important mechanism in converting molecular damage and stress into a broader call to the immune system for assistance in a specific location.

The interaction between cGAS and STING is one amongst a number of innate immune pathways that sense molecular damage. cGAS is a sensor for DNA in the cytosol, and its interaction with STING then drives the consequence changes in cell state and inflammatory signaling. Researchers are increasingly interested in the cGAS-STING pathway as a target to suppress maladaptive overactivation of the immune system in aged tissues and inflammatory diseases. Unfortunately, as for all such efforts at present, cGAS-STING interactions are also involved in the normal, beneficial activation of the immune system. This presents challenges and limits the use of a very aggressive suppression of those regulatory systems known to be involved in the chronic inflammation of aging. Better approaches are needed, aimed at removing the damage of aging that causes of STING activation.

Photoaging: UV radiation-induced cGAS-STING signaling promotes the aging process in skin by remodeling the immune network

Excessive exposure of the skin to UV radiation (UVR) accelerates the aging process and leads to a photoaging state which involves similar pathological alterations to those occurring in chronological aging. UVR exposure, containing both UVA and UVB radiation, triggers cellular senescence and a chronic inflammatory state in skin. UVR promotes oxidative stress and a leakage of double-stranded DNA (dsDNA) from nuclei and mitochondria into the cytoplasm of keratinocytes and fibroblasts. It is recognized that cytosolic dsDNA is a specific danger signal which stimulates cytoplasmic DNA sensors. The activation of the signaling through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) is a major defence and survival mechanism combatting against tissue injuries.

There is abundant evidence that UVR exposure of skin stimulates cGAS-STING signaling which promotes cellular senescence and remodels both the local and systemic immune network. cGAS-STING signaling activates the IRF3 and NF-κB signaling pathways which trigger both pro-inflammatory and immunosuppressive responses. Moreover, cGAS-STING signaling stimulates inflammatory responses by activating the NLRP3 inflammasomes. Senescent fibroblasts secrete not only cytokines but also chemokines and colony-stimulating factors which induce myeloid differentiation and recruitment of immune cells into inflamed skin.

Photoaging is associated with an immunosuppressive state in skin which is attributed to an expansion of immunosuppressive cells, such as regulatory T cells. UVR-induced cGAS-STING signaling also stimulates the expression of PD-L1, a ligand for inhibitory immune checkpoint receptor, which evokes an exhaustion of effector immune cells. There is clear evidence that cGAS-STING signaling can also accelerate chronological aging by remodeling the immune network.

Some forms of respiratory infection can cause lasting issues and loss of function. It has been suspected that an increased burden of senescent cells is one of the mechanisms involved in post-infection effects. While senescent cells are created constantly throughout life, a population of lingering senescent cells grows with age to disrupt tissue structure and function via inflammatory signaling. An increase in this burden of senescent cells is already known to cause increased mortality and risk of age-related disease in cancer survivors treated with chemotherapy and radiotherapy, so it should not be surprising to find this outcome occurring in other conditions and treatments that place a great deal of stress on cells for an extended period of time.

Influenza A virus (IAV) infection causes acute and long-term lung damage. Here, we used immunostaining, genetic, and pharmacological approaches to determine whether IAV-induced cellular senescence causes prolonged alterations in lungs. Mice infected with a sublethal dose of H1N1p2009 exhibited cellular senescence, as evidenced by increased pulmonary expression of p16, p21, β-galactosidase and the DNA damage marker gamma-H2A.X. Cellular senescence began 4 days post-infection (dpi) in the bronchial epithelium, then spread to the lung parenchyma by 7 and 28 dpi (long after viral clearance), and then declined by 90 dpi. At 28 dpi, the lungs showed severe remodeling with structural bronchial and alveolar lesions, abrasion of the airway epithelium, and pulmonary emphysema and fibrotic lesions that persisted up to 90 dpi.

In mice and nonhuman primates, persistence of senescent cells in the bronchial wall on 28 dpi was associated with abrasion of the airway epithelium. In p16-ATTAC mice, depletion of p16-expressing cells with AP20187 reduced pulmonary emphysema and fibrosis and led to complete recovery of the airway epithelium at 28 dpi, indicating a marked acceleration of the epithelial repair process. Treatment with the senolytic drug ABT-263 also accelerated epithelial repair without affecting pulmonary fibrosis or emphysema. These positive effects occurred independently of viral clearance and lung inflammation at 7 dpi. Finally, AP20187 treatment of p16-ATTAC mice at 15 dpi led to complete recovery of the airway epithelium at 28 dpi.

Thus, virus-induced senescent cells contribute to the pulmonary sequelae of influenza; targeting senescent cells may represent a new preventive therapeutic option.

Link: https://doi.org/10.1111/acel.70140

Infectious disease is a major cause of late life mortality, the result of the age-related decline of immune function. The sizable investment in time and funding that goes into efforts to enhance the efficacy of vaccines in older adults is one example of the costs of attempting to cope with the consequences of aging. Developing new vaccines and better vaccination techniques is an expensive process. Yet coaxing the aged immune system into greater efforts via the use of adjuvants and other more sophisticated vaccine engineering cannot produce the degree of benefit that a much more crude vaccination will produce in a younger adult - one is inherently limited by the aging of the immune system. This is one of many areas in which rejuvenation of youthful function is a far better goal to aim for.

Older persons (65 and above) comprise the world´s fastest-growing age group today. Enabling older individuals to live independently, remain socially engaged, and manage or prevent chronic illnesses contributes to reducing healthcare costs and improving overall quality of life. Infectious diseases are a major cause of morbidity and mortality in the older population. In 2021, COVID-19 alone was the third most frequent cause of death for people over 65 (10.9% of all deaths) in the EU. This highlights the devastating effect infectious diseases can have on older populations. Co-morbidities, such as chronic heart or lung disease and diabetes, further increase the risk for severe infections.

The overall morbidity of infectious diseases in older adults is frequently underestimated. In addition to the immediate impact of the acute disease, there are several other risks and sequelae associated with infections in this age group. Many older persons do not recover fully after an acute episode of infection. A study in Canada reported 12% mortality in patients aged 65 and older hospitalized for influenza infection, and 20% suffered a decrease in their functional status (9% moderate decrease, 11% catastrophic disability) after recovery.

Therefore, preventing infectious disease is an important measure to ensure healthy aging and preserve the quality of life. Vaccines against influenza and pneumococcal disease have long been available. This review focuses on novel developments regarding vaccines for older adults including strategies to improve and advance existing vaccines and the recent development of vaccines against additional pathogens, such as Respiratory Syncytial virus. There are still many additional pathogens, for which vaccines are highly desirable for older adults. Age-associated changes of the immune system can impair the immunogenicity and protective effect of vaccines and therefore specific strategies to protect this vulnerable population are necessary.

Link: https://doi.org/10.1080/21645515.2025.2517931

Mitochondria are power plants, hundreds of these organelles in every eukaryotic cell, descended from ancient symbiotic bacteria, and now repurposed to generate the chemical energy store molecule adenosine triphosphate (ATP) that is used to power cell processes. Beneath this simple overview lies a very complex and incompletely understood biochemistry. Mitochondria influence many core cell processes, and are influenced in turn. The oxidative byproducts generated by ATP production are both damaging and a signal that can be beneficial. Mildly impairing mitochondrial function can be beneficial to health, if accomplished in certain ways. And so forth. It is clearly the case mitochondria become dysfunctional in cells in aged tissues, as measured in many different ways, and this appears to be an important contribution to the aging process. What to do about it is unclear, however.

The best of presently available pharmacological and supplement based approaches that improve mitochondrial function or improve the quality control process of mitophagy responsible for clearing damaged mitochondria struggle to much improve on the benefits of exercise. It is also quite unclear in most cases as to how exactly they function to achieve this outcome, and bear in mind that the relevant biochemistry is itself still incompletely mapped out and understood. The most impressive results instead emerge in animal studies of partial reprogramming on the one hand, to reset expression of proteins necessary for mitochondrial function to youthful levels, and mitochondrial transplantation on the other, delivering functional young mitochondria for cells to make use of. Both of these technologies remain in relatively early stages of development, still far from the clinic.

Mitochondrial dysfunction in the regulation of aging and aging-related diseases

Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence.

In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responses that are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence.

Senescent cells accumulate in the aged body, generating a potent mix of pro-inflammatory signaling known as the senescence-associated secretory phenotype (SASP) that is disruptive to tissue structure and function. Over the last decade or so, researchers have devoted an increasing amount of time and effort into firstly understanding these cells, and secondly finding potential ways to reduce their contribution to age-related disease and mortality. While most efforts are directed towards the selective destruction of senescent cells via senolytic therapies, a growing number of projects are identifying senomorphic therapies that might reduce the SASP, and thereby reduce the harmful impact of lingering senescent cells. Such therapies would have to be taken continuously versus the intermittent use of senolytics, but nonetheless papers such as the one noted here are emerging on a regular basis.

Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age-related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored.

By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment.

Together, our study supports the feasibility of exploiting a redox-active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof-of-concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age-related conditions. Prospective efforts are warranted to determine long-term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.

Link: https://doi.org/10.1111/acel.70138

Researchers have investigated the favorable effects of hydrogen sulfide (H2S) on cell metabolism in the context of aging. An increased presence of H2S appears to modestly improve mitochondrial function and autophagy to some degree, thereby reducing oxidative stress and inflammation characteristic of aging. This functions via post-translational modification of important proteins via S-sulfhydration, changing their function. Like most approaches to metabolic manipulation, the effect size is not as large as we might like it to be, and the underlying biochemistry may overlap to some degree with responses to exercise and calorie restriction.

Hydrogen sulfide (H2S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial biosynthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.

The age-related decrease in endogenous H2S synthase leads to a decline in the level of S-sulfhydration modification of cysteine residues in target proteins, which ultimately promotes the accumulation of reactive oxygen species (ROS) in an age-dependent manner, thereby triggering DNA damage. Moreover, the reduction in intracellular protein S-sulfhydration is correlated with an age-related secretory phenotype, characterized by heightened secretion of inflammatory factors and chemokines, as well as impairment of the autophagy-lysosomal pathway. This leads to the onset of systemic chronic inflammation and ultimately contributes to inflammaging.

To date, numerous studies have emphasized the potential role of protein S-sulfhydration in addressing age and stress-related inflammatory disorders. In disease models such as arthritis and myocardial ischemia reperfusion injury (IRI), supplementation with exogenous H2S donors can effectively counteract cell senescence by promoting the nuclear entry of KEAP1/NRF2, reducing the membrane stability of the receptor RAGE, inhibiting the S-sulfhydration of the NF-κB p65 subunit, and decreasing oxidative stress along with the release of inflammatory factors. Nevertheless, there is a paucity of effective therapeutic interventions targeting age-related pathways. In this review, we offer a comprehensive overview of the current understanding of S-sulfhydration and its role in combating oxidative-inflammatory stress and cellular aging.

Link: https://doi.org/10.1016/j.jare.2025.06.038