Fight Aging! Newsletter, October 10th 2022

WHO had proposed the inclusion of the term "old age" in ICD-11. Ageing is not a pathological process and is globally accepted as a normal human attribute, with longevity being a privilege that we all hope to enjoy. The new "old age" label in ICD-11 was intended to replace the R54 code of "senility", previously used in ICD version. The decision to replace the R54 code resulted from increasingly negative connotations around the term "senility". An additional extension code (XT9T) was included in the causality section of ICD-11, which defined "ageing-related" as "caused by pathological processes which persistently lead to the loss of organism's adaptation and progress in older ages". The intention for including the additional code was to provide a greater focus on the biological aspects of ageing in global health policy and better opportunities for the development of new biological therapies. However, because of societal ageism, and because biological ageing and chronological ageing are not synonymous, the addition of these two codes left the ICD-11 proposal with potential for unintended negative consequences.

To be clear, WHO's inclusion of "old age" in ICD-11 was not intended to cast age or ageing as a disease, nor to consider ageing in terms of the number of years since birth, or greater than a particular age category. The intention was to recognise that the physiological process of ageing has a detrimental effect on a person's intrinsic capacity. In the context of healthy ageing, "ageing associated decline in intrinsic capacity", in very sharp contrast to the diagnosis of "old age", would be fully aligned with and reflect the ICD's purpose, and accomplish the ICD's envisioned resolutions. With global ageing, an urgent imperative exists to accurately assess population health and to holistically target maintenance and optimisation of physical and cognitive function, which would also be possible by enhancing ICD's reporting system with use of the term "ageing associated decline in intrinsic capacity". We believe there would be a substantial shift of focus with use of this term, from a static to a dynamic assessment of the person's health and capacity across a life trajectory.

The latest version of the International Classification of Diseases, ICD11, supports installed new dynamics in the nascent field of longevity medicine by classifying ageing as a disease. It allows physicians to target ageing in a comprehensive rather than a less efficacious disease and syndromes-oriented manner. Researchers have called for excluding old age from ICD-11, suggesting replacement by frailty.

Whether the term old age is the best choice of terminology for a state of multi-malfunction is a semantic, redundant debate. First, ICD codes are carefully considered and revised before being implemented. Secondly, frailty refers to, mostly but not exclusively, age-related disabilities, although old age is not always associated with frailty. Thus, these terms are not mutually exclusive and can co-exist in the ICD, as a part of a hierarchy of causation. The extension code XT9T guarantees coding for measurable age-related processes - eg, inflammageing, mitochondrial dysfunctions, etc.

The MG2A code, on the other hand, is representative of the paradigm shift in the definition of an individual's age, from chronological to biological, and will promote the development of therapies to optimise biological age. This paradigm shift in the definition of age, along with technological advances in the ability to control biological age, has led to considerable investment in the field of longevity to develop interventions targeting ageing mechanisms and systemic rejuvenation rather than a single organ or system at a time.

The nematode C. elegans begin adulthood vigorously exploring their environment. Over time, they slow and stop crawling, a behavioural stage known as vigorous movement cessation (VMC). VMC is a biomarker of ageing and a proxy for nematode health. Studies of genetically identical nematodes have shown it is a powerful predictor of a worm's lifespan, but at the same time, interventions designed to alter ageing can disproportionately affect VMC in comparison to lifespan and vice versa.

Researchers developed the 'Lifespan Machine', a device that can follow the life and death of tens of thousands of nematodes at once. The worms live in a petri dish under the watchful eye of a scanner that monitors their entire lives. By imaging the nematodes once per hour for months, the device gathers data at unprecedented statistical resolution and scale. The research team found that nematodes have at least two partially independent ageing processes taking place at the same time - one that determines VMC and the other determines time of death. While both processes follow different trajectories, their rates are correlated to each other, in other words, in individuals for whom VMC occurred at an accelerated rate, so did time of death, and vice versa. In other words, the study revealed that each individual nematode has at least two distinct biological ages.

The study calls into question a crucial assumption of ageing biomarkers, that when interventions such as exercise or diet "rejuvenate" a biomarker, it's a good sign that the underlying biology of ageing has similarly changed. "Our model shows that biomarkers can be trivially decoupled from outcomes because they measure an ageing process that is not directly involved in the outcome but simply correlates with it in a system of hierarchical processes. In simple terms, just because two parts of an individual tend to correlate in their biological age across individuals, it doesn't mean that one causes the other, or that they are likely to involve shared ageing mechanisms."

Individuals who remain vigorous longer tend to live longer, supporting the design of predictive behavioral biomarkers of aging. In C. elegans, the timing of age-associated vigorous movement cessation (VMC) and lifespan correlate strongly between individuals. However, many genetic and pharmaceutical interventions that alter aging produce disproportional effects on VMC and lifespan, appearing to "uncouple" the rate of behavioral aging and lifespan. To study the causal structure underlying such uncoupling, we developed a high-throughput, automated imaging platform to quantify behavioral aging and lifespan at an unprecedented scale.

Our method reveals an inverse correlation between each individuals' vigorous movement span and their remaining lifespan. Robust across many lifespan-altering interventions, our data shows that individual C. elegans experience at least two distinct but coupled physical declines - one governing VMC and the other governing lifespan. Through simulations and modeling, we clarify the causal relationship between these two "biological ages" and highlight a crucial but often untested assumption in conventional aging biomarker research: predictive biomarkers may not always report on the same biological age as that which determines long-term health outcomes.

Eisai and Biogen yesterday announced positive topline results from the Phase 3 Clarity trial of their anti-amyloid antibody lecanemab. The drug slowed decline on the primary endpoint, CDR-SB, by 27 percent over 18 months, and also nudged down decline on all secondary clinical endpoints. The incidence of the brain edema known as ARIA-E was 12.5 percent, about one-third of that seen with Biogen's approved anti-amyloid antibody Aduhelm. That said, researchers also noted the absolute difference in CDR-SB scores was small, at 0.45, with some questioning how clinically meaningful this is. In the bigger picture, researchers said the data strengthen the amyloid cascade hypothesis. "This confirms the importance of Aβ in disease pathogenesis. This is the first time a therapeutic antibody has clearly changed the course of Alzheimer's disease. It is a pivotal moment in the history of Alzheimer's therapy."

In the study, people getting lecanemab still had cognitive decline, but it progressed 27% slower than in those on a placebo. That translates to 0.45 points on the 18-point CDR-SB. Although the difference is modest, it's spawning hope. "This does make us feel a little better. These drugs do work." Lecanemab had side effects, most notably certain brain abnormalities seen with other anti-amyloid therapies, including swelling and small hemorrhages in the brain. Neuroimaging turned up these concerns in about 21% of patients on lecanemab, and 9% of those on the placebo. Although these abnormalities often produce no symptoms, about 3% of those getting lecanemab did have symptoms from them.

Doctors aren't sure how the apparently gentler slope of cognitive decline would be perceived by patients and their families. "Does that mean that grandma is going to have a few better days, a few better months, a few better years? It's still an open question." Commenters hesitate to make grand pronouncements, especially after last year's flameout of aducanemab. "We're all feeling a sense of wariness and caution. We want to dig into the data before we make any large conclusions."

Eight of the 35 agents tested by the ITP have significantly increased lifespan in one or both sexes. None has shortened lifespan. Five of the 8, that is, nordihydroguaiaretic acid (NDGA), aspirin, 17-α-estradiol (17E2), Protandim, and canagliflozin have increased lifespan only in males. None of the agents tested to date has increased lifespan only in females. Three agents led to significant lifespan increase, but with varying degrees of sex-specificity. Glycine, for example, led to small but similar increases, significant in both sexes. Acarbose effects were more dramatic in males than in females at any of the three tested doses, and if started later in life, that is, at 20 months of age. Rapamycin, over a range of doses and at two starting ages, has had strong positive effects in both sexes, but at a given dose in chow typically leads to a larger percentage increase in female than in male mice, Five of the agents that increase lifespan (NDGA, aspirin, rapamycin, 17E2, and acarbose) have been re-examined in later cohorts with different dosages and treatment durations. Of these, only aspirin did not replicate, although it was only tested at higher doses.

The ITP has also begun to test combinations of lifespan-extending agents for potential additive effects. Metformin and rapamycin were tested in combination based on the hypothesis that the insulin-sensitizing action of metformin might compensate for the potentially deleterious insulin desensitizing effect of rapamycin and potentially different mechanisms of action of the two agents might have additive effects on survival. The results were not entirely clear-cut because in both sexes the combination of metformin and rapamycin led to a larger percentage benefit compared with simultaneous controls than had been seen in previous studies of rapamycin alone, but the benefit of the combination over rapamycin-only historical controls was not statistically significant. Here, we extend this strategy, testing rapamycin and acarbose in combination, starting at 9 or 16 months of age, based on a similar rationale to that used for the metformin/rapamycin trial.

In male mice, the combination of rapamycin and acarbose produced a larger absolute and percentage change in survival than that seen in mice that had, in previous years, received the same dose (14 ppm) of rapamycin alone. Rapamycin-treated males in the previous C2006 cohort lived, on average, 10% longer than simultaneous controls (average of values at each site), and in the previous C2009 cohort males lived an average of 5% longer than controls. The males in the current study dosed with rapamycin and acarbose lived 19% longer, more than twice the percent change seen in either of the two earlier studies.

Changes in cardiac structure and function occur with ageing and may lead towards ageing-related cardiovascular disease. Recent explorations into intestinal microbiota have provided important insights into shifts in microbial composition that occur in response to cardiovascular disease pathogenesis. Several proposed mechanisms include altered gut permeability, endotoxemia, and the systemic effect of metabolites including trimethylamine (TMA), short-chain fatty acids (SCFA), and secondary bile acids. However, causal associations between gut microbes and left ventricular (LV) function have yet to be proven. We sought to determine whether gut microbial composition is associated with left ventricular myocardial relaxation, an early manifestation of myocardial ageing, among older adults.

Among n = 15 participants (53% males, mean age 75 ± 4 years) recruited as part of a community-based research study on myocardial ageing, subjects with normal LV ejection fraction (60% and above) on baseline echocardiography were selected to undergo gut microbial composition examination in this proof-of-concept cross-sectional study. Myocardial ageing was assessed to be more impaired in those subjects with lower calculated ratios of peak early (E) to late diastolic (A, atrial contraction) velocities on Doppler echocardiography. We compared metagenomic reads between older adults with myocardial ageing (n = 8) vs. those without myocardial ageing (n = 7), based on E/A ratios.

Older adults with cardiac ageing had higher levels of several pathogenic gut bacteria. Ruminococcus, of the phylum Firmicutes, have been associated with higher C-reactive protein levels and higher pulse wave velocity. Certain Ruminococcus species are also capable of producing TMA, which has been linked to atherosclerotic disease and heart failure. Several Paraprevotella species, including P. xylaniphila, can produce pro-inflammatory metabolites, such as succinic acid, and is also associated with hypertension, metabolic diseases, and inflammatory diseases. Increase in gut Paraprevotella has been observed in association with the development of heart failure in mice.

Among individuals without cardiac ageing, we found higher levels of Firmicutes bacteria. Firmicutes are producers of SCFAs that regulate cholesterol levels, and some species have been associated with higher serum HDL. Reduced levels of Firmicutes were associated with LV hypertrophy and progression to heart failure in rats. In conjunction with higher levels of Bacteroidetes bacteria seen in our samples with cardiac ageing, we speculate that the balance between Firmicutes and Bacteroidetes (i.e., ratio) may be useful for studying gut microbial composition in relation to myocardial ageing in the future.

Peripheral artery disease (PAD) affects more than 7% of Americans over age 40 and more than 29% of those over 70. The disease can cause pain when walking, coldness or numbness in the lower leg, painful leg or arm cramps, and difficulty sleeping, among other symptoms, though it also may cause no symptoms at all. The lack of adequate blood flow to the limbs may make it difficult for wounds to heal and can, in severe cases, lead to amputation. Existing treatments include medicine to improve blood flow and manage pain; for appropriate cases, doctors may also consider options such as surgery or the placement of a stent to open clogged arteries.

Researchers were able to use a new magnetic-resonance imaging (MRI) technique at the end of exercise to understand the effects of PAD in the calves of patients with the disease and distinguish them from normal volunteers. The approach they used, called chemical exchange saturation transfer, or CEST, produced results comparable to the current gold standard. CEST, they found, offered added benefits without requiring highly specialized equipment unavailable to many hospitals and researchers. "The beauty of CEST is that it creates an image of energy stores in the muscle which we can match to images of blood flow. This gives us a new understanding of how atherosclerosis in the leg arteries causes problems in the muscles downstream."

The link between human health and the gut microbiome is profound and has been speculated upon for thousands of years. In 400 B.C., it was suggested by Hippocrates that "bad digestion is the root of all evil" and "death sits in the bowels". It is now well-known that humans are inhabited by microorganisms, including bacteria, viruses and archaea, that live in harmony with them. Many aspects of human health are also influenced by the gut microbiota, as they may provide energy and nutrients to the host by aiding the digestion of nondigestible dietary components and can also contribute to inflammation, infection, gastrointestinal diseases, diabetes mellitus, and obesity. Interestingly, the composition of the human gut microbiota shifts with age, leading to influenced changes in the host's health. In this regard, the disturbance of the microbiome has been suggested as a new hallmark of ageing.

Diet can be used to modulate the composition of gut microbiota. An abundance of short-chain fatty acids, which are produced by gut microbes and have been shown to exhibit protective roles against a panoply of diseases, has been shown to correlate with diet. It was shown that as compared to an animal-based diet, vegan and vegetarian diets which comprise greater intake levels of fibre, resulted in higher levels of short-chain fatty acids. Interestingly, calorie restriction is known as the only experimental procedure that can, in various animal models, effectively lengthen lifespan. In a study that studied the shift in gut microbiota induced by a high-fat diet versus a low-fat diet in mice, it was demonstrated that mice with a 30% restriction of low-fat diet had a unique gut microbiota, indicating that modulation of the gut microbiota can be achieved by restricting the intake of diet.

Prebiotics - nondigestible food ingredients that are metabolized by selective intestinal microorganisms - can be used to modulate the gut microbiota to increase the abundance and activities of beneficial bacteria. Prebiotics resist digestion in the small intestine to reach the colon, where they are acted upon by gut microflora, leading to specific changes in composition and activity in the gut microbiota. Probiotic supplementation has been applied in the modulation of the gut microbiota to convey health benefits. Probiotics are defined as live microorganisms that confer to improve the health of the host when adequate amounts are administered in a safe and efficacious manner. Several studies have supported the use of probiotic supplementation for its therapeutic effects against a broad range of diseases, especially for metabolic and gastrointestinal disorders. In addition, the ability of probiotic supplementation to modulate the gut microbiota was reported in terms of faecal bacterial community structure being significantly different as compared to placebo.

Faecal microbiota transplantation is the administration, into a recipient's intestinal tract, of the whole microbiota from healthy donor faeces to modify or normalize intestinal microbiota composition. The ability of faecal microbiota transplantation to treat several diseases, including irritable bowel syndrome, metabolic diseases, autoimmune diseases, constipation, neuropsychiatric conditions, colon cancer, chronic fatigue syndrome, and allergic disorders, has been reported. The ability of faecal microbiota transplantation to treat Clostridioides difficile infection in the elderly (85 years old and above) was recently investigated, and the report indicated that severe infections in all cases were improved following one faecal microbiota transplantation, indicating that "frail older people" might benefit from faecal microbiota transplantation.

It is now clear that the age-related dysbiosis of the gut microbiota may lead to unhealthy ageing, contribute to the development of comorbidities and may even dictate the lifespan of individuals, as shown in the previous sections. Hence, by inducing changes in the gut microbiota, it might be possible to improve the health of the elderly and even prolong their lifespan.

The role of amyloid-β (Aβ) in Alzheimer's disease (AD) is debated: some argue Aβ takes center stage as the principal actor; others contend it is merely a spectator in the pageant of pathologies that typify AD. Nonetheless, a diversity of data (including in vitro neurotoxicity studies and genetic linkage analyses) do compellingly link Aβ to AD's pathology. Accordingly, rather than unconditionally rejecting the role of Aβ (or any other proposed specific disease mechanism), the need for an innovative broadly encompassing model of AD, which harmonizes multiple divergent theories into a single unified comprehensive explanation, emerges as a much-needed milestone on the road to a cure.

Herein, such a broad new molecular-level model of AD is proposed: "Alzheimer's disease as an autoimmune disease" ("AD-squared" or "AD2"). In the AD2 model, AD is explained as a brain-centric disorder of innate immunity involving concurrent autoimmune and autoinflammatory mechanisms. Although AD2 still includes Aβ as an important molecular player, it rejects the "amyloid misfolding hypothesis" per se, instead recognizing Aβ as a physiologically oligomerizing cytokine-like immunopeptide, which is merely one part of a much larger, comprehensive, highly interconnected immunopathic conceptualization of AD.

The AD2 model may be summarized as follows: in response to diverse pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) immune-stimulating events (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is physiologically biosynthesized and released as an early responder immunopeptide, and triggers an innate immunity cascade in which oligomeric Aβ exhibits both immunomodulatory and antimicrobial properties. The immunomodulatory properties of Aβ (mediated via Aβ's oligomeric interactions with TREM2, glycosaminoglycan, and NLRP3 receptors) augment ongoing microglial activation and pro-inflammatory cytokine release thereby ultimately contributing to apoptotic neuronal death via non-specific autoinflammatory processes in which bystander neurons are killed.

Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro.

Our results suggest several scenarios by which senescent cell targeting may beneficially influence brain immune cell composition. First, p16-positive brain myeloid cells (resident microglia and infiltrating myeloid cells) may drive peripheral immune cell recruitment, and their targeting may prevent a shift to homeostatic imbalance, characterized by infiltration of activated, potentially senescent, circulating inflammatory cells. Second, other senescent cell types (e.g., p16-positive astrocytes, oligodendrocytes, and endothelial cells) may also exert proinflammatory influence and may also be cleared. Third, reducing the abundance of circulating senescent immune cells may thereby deplete the pool available for recruitment into the brain under steady-state inflammatory conditions. Fourth, systemic senescent cell elimination may reduce the abundance of senescent cells throughout the body that contributes senescence-associated secretory phenotype (SASP) factors to the circulating progeronic proteome, which is a driver of age-related brain dysfunction.

Based on the established influence of circulating senescent inflammatory cells and SASP factors as mediators of organ homeostasis, we assert that rejuvenation of the inflammatory brain cell landscape and associated improvements in cognitive function following clearance of p16-positive cells in aged mice may reflect a combination of senescent cell elimination in the brain, periphery, and circulation.

Persistent DNA lesions build up with aging triggering inflammation, the body's first line of immune defense strategy against foreign pathogens and irritants. Once established, DNA damage-driven inflammation takes on a momentum of its own, due to the amplification and feedback loops of the immune system leading to cellular malfunction, tissue degenerative changes, and metabolic complications.

There is much work to be done before we will be able to dissect the functional links between persistent DNA damage and inflammation in vivo. The use of progeroid murine models with tissue-specific defects in genome maintenance will allow us to further delineate the causal contribution of specific cell types to systemic inflammation with old age. In parallel, animal models with tagged DNA repair factors coupled to functional genomics and proteomics strategies may prove valuable for identifying new gene targets or protein partners that could link genome maintenance with innate immune signaling. It will also be essential to identify how an active DNA damage response originating from any alterations in the physicochemical structure of the DNA activates cytoplasmic stress responses and the release of proinflammatory factors in the tissue microenvironment.

Likewise, it will be vital to dissect the functional links between DNA damage-driven chronic inflammation and metabolic rewiring with old age. Finally, the recent development of novel therapeutic strategies indicates that, in the long run, it may be more valuable to invest in approaches targeting the DNA damage itself rather than suppressing downstream proinflammatory signals. Such strategies could open new, meaningful avenues towards the development of new rationalized therapeutic interventions against a wide range of adverse pathological outcomes during aging

As long as there have been humans, there has been death. There's evidence that funeral rituals may date back hundreds of thousands of years, so it's likely our species has grappled with its finitude for at least tens of millennia. Is knowing it will end what motivates us to succeed, or provides meaning at all? The first thing to say is that this is one of many objections that demonstrate how we put ageing research into its own ethical category - no-one would ask a cancer researcher whether they're concerned that a reduction in death arising from their research might negatively affect the human condition, and yet, for ageing biologists, this is a common query.

Much of the meaning in our lives comes from the people that fill it, our families and friends. And much of the pain, both emotional and physical, results from ill health, either theirs or our own. If we were all living longer lives in good health, as medicines against ageing promise, why wouldn't we want to continue living? And as art, music, science, technology and more continue to advance (perhaps to new places only possible thanks to creators or researchers with extended careers, able to make discoveries only possible with extra decades of experience), it seems incredibly unlikely that we'd get bored.

And, even if we do tire of life itself aged 250, wouldn't you rather go in a short, painless manner at a time of your own choosing, rather than having life slowly and painfully taken from you over decades by the ageing process? The key point is that medicines for ageing are just that - medicine. They're no stranger than a heart disease researcher trying to prolong healthy life by creating a drug to lower cholesterol. There's no real evidence that the extra years bought by preventing heart attacks have stripped modern life of its meaning - so why would adding a few more years free from heart attacks and cancer and frailty do so?

Ageing is regulated by intrinsic genetic pathways and in response to extrinsic environmental cues. Diet and temperature are widely reported to modulate longevity through a network of molecular signalling. The magnetic field is another critical environmental factor to all life on earth, which has a mild dipolar geomagnetic field (GMF) of 25-65 μT. Whereas artificial magnetic fields of high energy are hazardous by ionizing and thermal effects, GMF is known to have many significant biological effects. Magnetotactic bacteria sense GMF for cellular migration. Other organisms across taxa, such as butterflies, salmon, and birds, are considered to navigate over long distances by tracing GMF. The moderate magnetic field has recently been shown to regulate immune cell function and redox homeostasis. Given its various biological effects, it is intriguing to explore the potential influence of the moderate magnetic field in ageing and the underlying mechanisms.

The nematode Caenorhabditis elegans is a well-established model organism in ageing research, with conserved ageing phenotypes and mechanisms. Adult C. elegans is around 1 mm in length and 31-72 μm in diameter. In lab, these tiny worms are grown on a two-dimensional bacteria lawn. These features make it easy to treat multiple worms and different worm tissues with similar magnetic field intensity. Moreover, C. elegans was suggested to sense GMF during vertical burrowing migrations. Here, we investigated the effect of a moderate magnetic field on worm ageing. Our results indicate that a static magnetic field (SMF) of 10 mT extends worms lifespan and enhances the motility of aged worms, potentially through inhibiting the ageing-related changes of mitochondrial morphology and function. We further found that SMF treatment upregulates a group of cytochrome P450 (CYP) genes to induce longevity.

CYPs have intensive interaction with mitochondria. Mitochondria is a major cellular organelle of CYPs localisation. The mitochondrial electron transport system serves as an electron donor for mitochondrial CYPs catalytic activity, whereas the products of CYP-dependent metabolism affect mitochondrial functions. CYP2U1, the mammalian ortholog of the three CYPs in SMF-induced longevity, is localised in mitochondria and controls mitochondrial morphology. As the three CYPs also regulate the morphological changes of mitochondria during worm ageing, it will be interesting to clarify their interaction with mitochondria further and to pursue the potential role of CYP2U1 in mammal ageing.

Researchers found that blocking the activity of the NALCN protein in cells in mice with cancer triggers metastasis. They also discovered that this process is not just restricted to cancer. To their surprise, when they removed NALCN from mice without cancer, this caused their healthy cells to leave their original tissue and travel around the body where they joined other organs. They found, for example, that healthy cells from the pancreas migrated to the kidney where they became healthy kidney cells. This suggests that metastasis isn't an abnormal process limited to cancer as previously thought, but is a normal process used by healthy cells that has been exploited by cancers to migrate to other parts of the body to generate metastases.

Despite being one of the main causes of death in cancer patients, metastasis has remained incredibly difficult to prevent, largely because researchers have found it hard to identify key drivers of this process that could be targeted by drugs. Now that researchers have identified NALCN's role in metastasis, the team are looking into various ways to restore its function, including using existing drugs on the market.

NALCN stands for sodium (Na+) leak channel, non-selective. Sodium leak channels are expressed predominately in the central nervous system but are also found throughout the rest of the body. These channels sit across the membranes of cells and control the amount of salt - that is, sodium - that goes in and out of the cell. Controlling this process also alters the balance of electricity across the cell membrane. It is not yet clear why these channels seem to be implicated so directly in cancer metastasis.

The study involved 318,752 people in the UK biobank database with an average age of 56. The participants did not have a history of stroke or cardiovascular disease at the start of the study. Researchers looked at people's exposure to air pollution based on where they lived at the start of the study. The participants were followed for an average of 12 years. During that time, 5,967 people had a stroke. Of those, 2,985 people developed cardiovascular diseases and 1,020 people later died. People exposed to high levels of air pollution were more likely to have a first stroke, post-stroke cardiovascular disease or death than people not exposed to high levels of pollution.

After adjusting for other factors that could play a role, such as smoking and physical activity level, researchers found that for each 5 micrograms per cubic meter (µg/m3) increase of fine particulate matter, for example, the risk of transitioning from being healthy to having a first stroke increased by 24% and from being healthy to dying the risk increased by 30%. Particulate matter consists of liquids or solids suspended in air. Fine particulate matter, PM2.5, is less than 2.5 microns in diameter and includes fly ash from coal combustion. Those who had a stroke during the study had an average exposure of 10.03 µg/m3 of PM2.5, compared to 9.97 µg/m3 for those who did not have a stroke. The researchers also found that the pollutants nitrogen oxide and nitrogen dioxide were associated with an increased risk of stroke and death.

Recent study reported that dynamic mitochondrial behavior, including the balance between fusion, fission, and movement, may play pivotal roles in regulation of mitochondrial activity. Mitochondria are transported along the actin cytoskeleton by specific motor proteins. The mechanical properties of the cytoskeleton significantly differ between old and young cells. The cytoskeleton exhibits increased stiffness and a decreased capacity to reversibly form in old cells. The mechanical properties of the cytoskeleton are important for transfer of mechanical signals. Therefore, both mechanical properties and cell stiffness linked with the cytoskeleton may be associated with mitochondrial functional activity in aging cells. However, the role of the actin cytoskeleton in mitochondrial dysfunction related with aging is unclear.

There are several lines of evidence that a relationship exists between the actin cytoskeleton and aging. Perturbed integrity of the actin cytoskeleton is connected with loss of mitochondrial function and aging. Several scientists have attempted to elucidate how modulation of the cytoskeleton can control aging. Chemical and biological stimuli and mechanical signals from extracellular environments can regulate cellular behaviors. Biophysical signals modulate the mechanical properties of the cytoskeleton. The mechanical properties of cells regulate cellular behaviors, such as proliferation, differentiation, and apoptosis. The mechanical properties of the cytoskeleton dramatically change with aging. Artificial disturbance of the cytoskeleton induces aging phenotypes, such as slow proliferation and increased mitochondrial dysfunction. Aged cells treated with a cytoskeleton stabilizer exhibit reversal of aging phenotypes due to recovery of mitochondrial functional activities.

Taken together, these findings demonstrate that the cytoskeletal stability is a key factor for reversal of aging.