Fight Aging!

Atherosclerosis is the name given to the growth of fatty plaques in artery walls. It is universal in later life, and the primary cause of human mortality via heart attack, stroke, heart failure, and so forth. Once a plaque grows past a given size, the mechanisms that caused its creation fade in importance in comparison to very simple feedback loop. The plaque is an inflammatory, damaged environment that attracts macrophage cells from the bloodstream and surrounding tissues. The macrophages attempt to ingest cholesterol and cell debris, passing the cholesterol back into the bloodstream to return to the liver for reuse or excretion, but instead become overwhelmed. The plaque environment and cholesterol excess forces macrophages into an inflammatory and dysfunctional state. The cells eventually die to add their mass to the plaque. A plaque is a macrophage graveyard, continually calling more macrophages to their doom.

Given this, some lines of research aim to make macrophages more resilient. In principle, if macrophages were not overwhelmed by excess cholesterol and other toxic aspects of the plaque environment, these cells would in time complete their task, dismantling the plaque and repairing the blood vessel wall. Nobody would die from atherosclerosis. A number of approaches have been suggested to at least modestly increase the resilience of macrophages to the plaque environment, and are in various stages of development. Today's open access paper adds another possibility to the list, another way to manipulate macrophage metabolism to sabotage the maladaptive reaction to the plaque environment in order to maintain repair activities.

Can enzyme behind high cholesterol be turned off?

"We found that by blocking the enzyme IDO1, we are able to control the inflammation in immune cells called macrophages." Inflammation plays a crucial role in the immune system, helping the body fight infections and heal injuries. But when inflammation becomes abnormal it can damage cells, disrupt normal functions and increase the risk of serious diseases. During these periods, macrophages can't absorb cholesterol properly, which can lead to chronic disease. Researchers found that the enzyme IDO1 becomes activated during inflammation, producing a substance called kynurenine that interferes with how macrophages process cholesterol.

When IDO1 is blocked, however, macrophages regain their ability to absorb cholesterol. This suggests that reducing IDO1 activity could offer a new way to help prevent heart disease by keeping cholesterol levels in check. The researchers also found that nitric oxide synthase (NOS), another enzyme linked in inflammation, worsens the effects of IDO1. They believe that inhibiting NOS could provide another potential therapy for managing cholesterol problems driven by inflammation.

HDLR-SR-BI Expression and Cholesterol Uptake are Regulated via Indoleamine-2,3-dioxygenase 1 in Macrophages under Inflammation

Macrophages play crucial roles in inflammation, and their dysfunction is a contributing factor to various human diseases. Maintaining the balance of cholesterol and lipid metabolism is central to macrophage function, and any disruption in this balance increases the risk of conditions such as cardiovascular disease, atherosclerosis, and others. The receptor HDLR-SR-BI (SR-BI) is pivotal for reverse cholesterol transport and cholesterol homeostasis. Our studies demonstrate that the expression of SR-BI is reduced along with a decrease in cholesterol uptake in macrophages, both of which are regulated by the activation of NF-κB.

Furthermore, we have discovered that indoleamine-2,3-dioxygenase 1 (IDO1), which is a critical player in tryptophan (Trp) catabolism, is crucial to the regulation of SR-BI expression. Inflammation leads to elevated levels of IDO1 and the associated Trp catabolite kynurenine (KYN) in macrophages. Interestingly, knockdown or inhibition of IDO1 results in the downregulation of lipopolysaccharide (LPS)-induced inflammation, decreased KYN levels, and the restoration of SR-BI expression as well as cholesterol uptake in macrophages. Beyond LPS, stimulation with pro-inflammatory cytokine IFNγ exhibits similar trends in inflammatory response, IDO1 regulation, and cholesterol uptake in macrophages. These observations suggest that IDO1 plays a critical role in SR-BI expression and cholesterol uptake in macrophages under inflammation.

Aging is an accumulation of forms of cell and tissue damage, and a complex network of downstream consequences of that damage that interact with one another to accelerate further dysfunction. It should not be too surprising to find that other approaches to producing damage in a living individual resemble aging, at least superficially. This is the case in DNA repair deficiency conditions, and, as researchers note here, it is the case in the aggressive use of chemotherapy to treat cancer.

While chemotherapy can be lifesaving, it also damages DNA and leads to cognitive issues known as "chemo brain." These effects resemble the memory and learning problems seen in older adults. There are several parallels in these two situations. In both, there is decreased blood flow in the brain when it is at rest and a smaller increase in blood flow when the brain is active. In addition, the blood-brain barrier, a protective layer that prevents harmful substances from entering the brain, is disrupted, which triggers inflammation in the brain. Finally, there is an accumulation of senescent cells in both brains. Senescent cells are in a suspended state of not being dead nor being able to fulfill their normal function, which also causes inflammation.

The research team studied several chemotherapy drugs in mice for their effects on the brain, including the commonly used paclitaxel and cisplatin. They found that even though the chemo drugs caused DNA damage in different ways, their characteristics were the same in how they affected cognition. Because of the blood-brain barrier, chemotherapy drugs do not directly enter and damage the brain. Instead, chemotherapy harms endothelial cells, the type of vascular cell most susceptible to damage. When the endothelial cells are impaired, they become senescent and produce inflammatory substances that compromise the blood-brain barrier.

The researchers also studied ways to improve cognition. They tested senolytics in aging mice. Senolytics are drugs that can induce senescent cells to die through apoptosis, the typical process by which cells are removed. By selectively removing senescent cells, cognition improved. Researchers took the study a step further to determine the ideal time window for administering senolytics to have the most positive effect on the brain's vasculature and cognition. They tested senolytics in mice of all ages and ultimately discovered the drug was most effective when the mice were about 16 months old, which researchers believe equates to 50 to 55 years old in humans.

Link: https://www.ou.edu/news/articles/2025/june/chemo-brain-and-the-Aging-brain-researchers-examine-similarities-in-search-for-improved-cognition

A burden of lingering senescent cells contributes to the chronic inflammation of aging and is disruptive to tissue structure and function. Excess visceral fat tissue is know to generate an increased burden of senescent cells. It does also dysregulate metabolism and provoke chronic inflammation in a range of other ways, however. So while senescent cells appear to be important in the damage done by obesity, it remains unclear as to what degree the use of senolytic drugs to selectively destroy senescent cells will reduce the consequences of obesity. Answers will emerge in time, but, as ever, making progress towards larger clinical trials and sufficient human data is a slow and expensive process. There is little incentive for industry to fund work on the existing cheap, off-patent senolytics, such as the dasatinib and quercetin combination, and the usual alternative path of developing and testing expensive, new, patented drugs takes as long as it takes.

Obesity and type 2 diabetes mellitus (T2DM) represent currently major health threats worldwide owing to their rapidly increasing prevalence and debilitating long-term chronic complications. Senescent cells play an important role in T2DM pathogenesis via direct impact on pancreatic β-cell function, since reduced pancreatic β-cell mass and subsequent defects in insulin secretion are major factors in the pathogenesis and progression of T2DM. Preferential accumulation of senescent cells in visceral adipose tissue (VAT) is then associated with an inappropriate expansion of adipocytes (hypertrophy), insulin resistance, and dyslipidemia and represents the nexus of mechanisms involved in aging and age-related metabolic dysfunctions. On the other hand, changes induced by long-standing, poorly controlled T2DM are linked to the accumulation of premature senescent cells in various tissues, contributing to the development of chronic irreversible complications. Thus, senescence is both a cause and a consequence of obesity and T2DM.

The presence of T2DM and its complications is the major reason for the massive financial burden of the treatment of T2DM. It is estimated that therapy of diabetic complications consumes up to two-thirds of the overall T2DM treatment costs. Despite the availability of novel glucose-lowering drugs, the number of patients with T2DM and related chronic complications keeps increasing at a high rate. Current pharmacological approaches address the pathophysiological defects present in T2DM rather than preventing the processes contributing to its development. Therapeutic targeting and elimination of senescent cells with suppression of the SASP production by senolytics may therefore be an effective strategy for a novel approach in the treatment of metabolic diseases.

Link: https://doi.org/10.3389/fcell.2025.1622107

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