Fight Aging!

A reduced calorie intake produces beneficial changes to metabolism, promoting autophagy and cell maintenance, among other mechanisms, improving health and leading to a modestly slowed pace of aging. Interestingly, adjusting the time of eating in order to experience longer periods of hunger while still consuming the same calorie intake produces outcomes that are broadly similar at the high level, even if somewhat different at the detailed level of metabolism and cell biochemistry.

One might look at the great breadth of research into calorie restriction, time-restricted feeding, and intermittent fasting and conclude that one of the more important factors in the results achieved is the amount of time spent in a state of hunger. In other words that it is the hunger-associated signaling and cellular reactions to that signaling that provide a sizable fraction of the benefits observed when calories are consistently reduced. There are, must be, other mechanisms at work, of course. A low calorie diet sustained over time reduces the burden of harmful inflammatory visceral fat tissue, for example. Further, reducing specific dietary components such as methionine without reducing overall calorie intake can trigger nutrient sensors to induce some of the benefits of calorie restriction. It is an interesting area of study.

Effect of time-restricted eating and intermittent fasting on cognitive function and mental health in older adults: A systematic review

Nutrition is one of the modifiable lifestyle factors that has been identified as a potential target for interventions in older adults' cognitive health and mental well-being. Time Restricted Eating (TRE) and Intermittent Fasting (IFA) are two dietary approaches that have gained popularity in recent years due to their potential health benefits. Time Restricted Eating (TRE), an approach rooted in the alignment of eating patterns with circadian rhythms, centers on limiting the span of time during which food consumption occurs each day and emphasizes the importance of when we eat, along with underscoring the intricate interplay between nutrition and the body's internal clock within a disciplined time frame typically ranging from 8 to 12 hours.

On the other hand, IFA encompasses a spectrum of fasting regimens with the common thread of cycling between periods of food consumption and periods of calorie restriction or fasting. These dietary approaches, TRE and IFA, have demonstrated their efficacy in improving metabolic health by enhancing factors such as insulin sensitivity, glucose metabolism, and lipid profiles. Additionally, these approaches have been associated with factors linked to increased longevity, including improvements in cardiovascular health and a reduction in the risk of age-related diseases.

Studies have suggested that both IFA and TRE may have beneficial effects on cognitive function and mental health in older adults. The mechanisms underlying these effects are complex and multifaceted, but may involve improvements in glucose metabolism, inflammation, oxidative stress, and neuroplasticity. Both IFA and TRE involve periods of fasting, which can lead to a decrease in insulin resistance and an increase in insulin sensitivity. This can, in turn, improve glucose uptake in the brain, which is important for preserving cognitive function and minimizing the risk of cognitive decline. Additionally, improved glucose metabolism may have a protective effect on the brain, lowering the likelihood of neurodegenerative conditions like Alzheimer's and Parkinson's. IFA and TRE may also modulate the gut microbiome, which has been implicated in brain function and mental health.

Recent studies have delved into the association between TRE, cognitive function, and mental health in older adults, yielding somewhat mixed results. While our findings suggest a relationship between TRE and IFA practices and cognitive function and mental health among older adults, it is important to acknowledge the complexity of this relationship. Various factors, including the duration and timing of the eating window and the physical condition of older adults, or even specific subgroups like those aged 70 years and older, can influence the outcomes.

Our systematic review encompasses a range of study designs, each offering unique insights into the effects of fasting interventions on cognitive function and mental health in older adults. Cross-sectional studies revealed that individuals practicing TRE were less likely to exhibit signs of mental health distress, particularly those aged over 70 years. Experimental designs provided preliminary evidence regarding the feasibility and potential efficacy of fasting interventions. Cohort studies tracked participants over time and found that individuals regularly practicing IFA were more likely to revert to successful aging with no cognitive impairment compared to those with irregular or no IFA practice.

In this study, researchers assessed the effects of a healthy lifestyle on mortality in older people suffering from chronic conditions of aging. As noted in similar studies, the effect size is larger than that achieved via readily available pharmaceutical strategies used to treat chronic illness, such as antihypertensive and lipid-lowering drugs. It is never too late to adjust one's choices in order to reduce future health risks: regular exercise, lose excess weight, eat a better diet, and so forth.

Lifestyles are associated with all-cause mortality, yet limited research has explored the association in the elderly population with multimorbidity. We aim to investigate the impact of adopting a healthy lifestyle on reducing the risk of all-cause mortality in older individuals with or without multimorbidity in both China and UK. This prospective study included 29,451 and 173,503 older adults aged 60 and over from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and UK Biobank. Lifestyles and multimorbidity were categorized into three groups, respectively. Cox proportional hazards regression was used to estimate the Hazard Ratios (HRs) and dose-response for all-cause mortality in relation to lifestyles and multimorbidity, as well as the combination of both factors.

During a mean follow-up period of 4.7 years in CLHLS and 12.14 years in UK Biobank, we observed 21,540 and 20,720 deaths, respectively. For participants with two or more conditions, compared to those with an unhealthy lifestyle, adopting a healthy lifestyle was associated with a 27%-41% and 22%-42% reduction in mortality risk in the CLHLS and UK Biobank, respectively; Similarly, for individuals without multimorbidity, this reduction ranged from 18% to 41%. Among participants with multimorbidity, individuals with an unhealthy lifestyle had a higher mortality risk compared to those maintaining a healthy lifestyle, with HRs of 1.15 and 1.27 for two conditions, and 1.24 and 1.73 for three or more conditions in CLHLS and UK Biobank, respectively. Adherence to a healthy lifestyle can yield comparable mortality benefits for older individuals, regardless of their multimorbidity status. Furthermore, maintaining a healthy lifestyle can alleviate the mortality risks linked to a higher number of diseases.

Link: https://doi.org/10.1016/j.ssmph.2024.101673

Given that cardiovascular disease is the largest cause of human mortality, and the present dominant strategy of lowering LDL-cholesterol in the bloodstream has failed to change that fact, it is perhaps surprising to find that there exist only minor, exploratory attempts to break new ground and move beyond this approach. There is not great program of discovery, no sense of urgency, only small groups occasionally trying something new every few years or so. More generally, research into novel ways to address aging and age-related disease is far from adequately supported, given the great burden of suffering and mortality that accompanies old age.

It is widely accepted that atherosclerosis, a primary driver of cardiovascular disease (CVD), is primarily caused by inflammation at the endovascular level, yet most treatments fail to address their cause. Aging itself is a major independent risk factor for CVD, which remains one of the leading causes of disability and death. As shown in different studies, age-related arterial dysfunction was found in the absence of conventional cardiovascular risk factors, suggesting that age-related arterial dysfunction is a primary effect of advancing age. This phenomenon persists despite best efforts to promote healthy lifestyle and pharmacological treatments. Additionally, it is worth noting that as much as 20% of individuals who develop coronary heart disease lack conventional risk factors. This suggests there are still unaddressed factors missing from the current approach to patient management. Furthermore, another study showed that up to 70% of individuals who experienced myocardial infarctions were classified as low risk based on conventional 10-year coronary heart disease risk screening.

Recent evidence suggests that three finite physiological responses to numerous insults exist in the human body, attributing to the pathophysiology of CVD: oxidative stress, inflammation, and ultimately vascular dysfunction. This process, often referred to as vascular aging or "inflammaging", encompasses the complex interplay of molecular and cellular events like immune dysregulation associated with aging and the acceleration of age-related diseases. Consequently, it is essential to consider certain overlooked and novel factors that contribute to aging as a process also contributing to the origin of traditional risk factors. For example, the gut microbiome - a complex ecosystem of organisms located throughout our body organs, including the gastrointestinal tract, serving as a transducer of environmental signals to the rest of the body - contributing either to promoting or reducing systemic inflammation and age-related cardiovascular disease risk. Understanding such factors is needed to be able to address them.

Link: https://doi.org/10.2147/CIA.S457180

As the authors of today's open access paper note, their study is not the first to find a correlation between the diversity of the oral microbiome and cognitive function. The relative numbers of different microbial species present in the mouth can be assessed using 16S rRNA sequencing, where different species have slightly different 16S rRNA gene sequences. Given low cost assays to categorize a microbiome, there is a growing interest in the contributions to function and dysfunction made by the various distinct microbiomes situated throughout the body: gut, skin, mouth, and so forth. In this case, a greater diversity of microbial species present in the mouth correlates with a lesser age-related loss of cognitive function. Why is this the case?

The most well researched mechanism is inflammation generated by harmful species such as Porphyromonas gingivalis, responsible for gum disease. Gum disease allows leakage of bacteria and their products into the bloodstream. There is some evidence for this mechanism to underlie a relationship between gum disease and more serious issues such as atherosclerosis and dementia, though there is some debate over whether this is in fact a sizable effect versus other contributing factors. It is possible to speculate in other directions, however. For example, people who take worse care of their oral health probably also undertake less day to day maintenance of health and fitness in other ways, leading to greater age-related neurodegeneration. Or that age-related loss of cognitive function may contribute to a lesser effort in maintaining oral health. The challenge with human epidemiological data is that it does not show causation.

Association of the oral microbiome with cognitive function among older adults: NHANES 2011-2012

An association between the gut microbiome and cognitive function has been demonstrated in prior studies. However, whether the oral microbiome, the second largest microbial habitant in humans, has a role in cognition remains unclear. Using weighted data from the 2011 to 2012 National Health and Nutrition Examination Survey, we examined the association between oral microbial composition and cognitive function in older adults. The oral microbiome was characterized by 16S ribosomal RNA gene sequencing. Cognitive status was assessed using the Consortium to Establish a Registry for Alzheimer's Disease immediate recall and delayed recall, Animal Fluency Test, and Digit Symbol Substitution Test (DSST). Subjective memory changes over 12 months were also assessed. Linear regression and logistic regression models were conducted to quantify the association of α-diversity with different cognitive measurements controlling for potential confounding variables. Differences in β-diversity were analyzed using permutational analysis of variance.

A total of 605 participants aged 60-69 years were included in the analysis. Oral microbial α-diversity was significantly and positively correlated with DSST (β = 2.92). Participants with higher oral microbial α-diversity were more likely to have better cognitive performance status based on DSST (adjusted odds ratio = 2.35) and were less likely to experience subjective memory changes (adjusted odds ratio = 0.43). In addition, β-diversity was statistically significant for the cognitive performance status based on DSST and subjective memory changes.

One potential mechanism underlying oral microbial dysbiosis and cognitive function impairment is systemic inflammation. A recent meta-analysis concluded that the concentrations of plasma or cerebrospinal fluid inflammatory markers were higher in patients with mild cognitive impairment than in normal control individuals. Indeed, alternations in the oral microbiome, a potential source of low-grade systemic inflammation, may contribute to the development of cognitive impairment and dementia. Periodontal disease, a condition known to be linked to oral microbial dysbiosis, has been correlated with elevated levels of neutrophil counts as well as proinflammatory mediators, such as interleukin (IL)-1, IL-6, and C-reactive protein in the blood. Conversely, intensive periodontal treatment resulted in an attenuation of systemic inflammatory markers.

This research makes for interesting reading in the context of a recent paper discussing a mismatch between brain and body circadian clocks as a contributing factor to degenerative aging. Researchers here show that an accumulation of senescent cells in the adrenal gland disrupts its adherence to circadian rhythm, while targeted removal of those cells restores function. We might add this to the many good reasons to remove lingering senescent cells from the aging body. These cells secrete a potent mix of pro-inflammatory factors that are disruptive to surrounding cell and tissue function, and are an important contributing cause of degenerative aging throughout the body and brain.

Aging progresses through the interaction of metabolic processes, including changes in the immune system and endocrine system. Glucocorticoids (GCs), which are regulated by the hypothalamic-pituitary-adrenal (HPA) axis, play an important role in regulating metabolism and immune responses. However, the age-related changes in the secretion mechanisms of GCs remain elusive. Here, we found that corticosterone (CORT) secretion follows a circadian rhythm in young mice, whereas it oversecreted throughout the day in aged mice older than 18 months old, resulting in the disappearance of diurnal variation. Furthermore, senescent cells progressively accumulated in the zona fasciculata (zF) of the adrenal gland as mice aged beyond 18 months. This accumulation was accompanied by an increase in the number of Ad4BP/SF1 (SF1), a key transcription factor, strongly expressing cells (SF1-high positive, SF1-HP).

Removal of senescent cells with the senolytic treatment of dasatinib and quercetin resulted in the reduction of the number of SF1-HP cells and recovery of CORT diurnal oscillation in 24-month-old mice. Similarly, administration of a neutralizing antibody against IL1β, which was found to be strongly expressed in the adrenocortical cells of the zF, resulted in a marked decrease in SF1-HP cells and restoration of the CORT circadian rhythm. Our findings suggest that the disappearance of CORT diurnal oscillation is a characteristic of aging individuals and is caused by the secretion of IL1β, one of the senescence-associated secretory phenotype factors, from senescent cells that accumulate in the zF of the adrenal cortex. These findings provide a novel insight into aging. Age-related hypersecretory GCs could be a potential therapeutic target for aging-related diseases.

Link: https://doi.org/10.1111/acel.14206

A considerable amount of effort has gone into assessing the biochemical differences between old people and extremely old people, in search of protective mechanisms that might be used as a basis for therapies to modestly slow the pace of aging. This may not be the best approach from the point of view of size of effect achieved at the end of the day, as centenarians are still meaningfully impacted by aging, their physiology far removed from that of a young individual, but it is an approach well suited to the present environment of low cost omics technologies. Everything that can be measured attracts attention, and the cheaper the measure is to enact, the more that researchers will use it.

Previous studies of the aging human brain have shown dynamic gene expression changes that distinguish young adults from the aging population. Independent transcriptome analyses showed shifts in the expression of different glial-specific genes and indicated that inflammatory or immune-responsive genes are upregulated during aging in most brain regions, increasing the vulnerability of the brain to cognitive aging. Moreover, a recent transcriptomic study performed in frontal cortex samples of individuals organized in two different groups according to their age (≤80 vs. ≥85 years) showed that the ≥85 years group of age was associated with a distinct transcriptome signature in the cerebral cortex and revealed a protective mechanism of aging and longevity mediated by neural circuit activity.

Centenarians are a group that exhibits extreme longevity, which is commonly accompanied by better quality of life, physical independence, and cognitive function compared to older individuals dying in 70s or 80s. Omic approaches in blood samples from centenarians revealed that the transcriptome and the expression pattern of noncoding RNAs are more similar to young individuals than septuagenarians. Different studies have also described that centenarians present a reduced number of cases with neurodegenerative diseases, in some cases avoid dementia. Consistent with these ideas, our recent study characterizing Basque centenarians identified that they showed better biological profiles in blood analysis, required fewer use of medical resources, and developed fewer diseases including from the nervous system compared with non-centenarians.

We performed transcriptomic studies in hippocampus samples from individuals of different ages (centenarians, here meaning those ≥97 years of age, old, and young) and identified a differential gene expression pattern in centenarians compared to the other two groups. In particular, several isoforms of metallothioneins (MTs) were highly expressed in centenarians. Moreover, we identified that MTs were mainly expressed in astrocytes. Functional studies in human primary astrocytes revealed that MT1 and MT3 are necessary for their homeostasis maintenance. The concentration of zinc in the brain surpasses that of the body by 10-fold and it is essential for normal functioning. There is a link between zinc levels in the brain and cognitive function, and the decline in cognitive performance observed during aging has been linked to the dysregulation of zinc homeostasis. MTs, zinc transporters family (ZnTs), presenilins, and zinc-regulated and iron-regulated proteins (ZIPs) are responsible for the homeostasis of zinc in the brain. Overall, these results indicate that the expression of MTs specifically in astrocytes is a mechanism for protection during aging.

Link: https://doi.org/10.1111/acel.14201

The practice of calorie restriction, reducing calorie intake to as much as 40% below ad libitum intake while still maintaining optimal micronutrient levels, is well demonstrated to slow aging in a range of species. Relative extension of life span is smaller as species life span increases, however, for reasons that make sense from an evolutionary perspective. It is unclear as to how the observed, sweeping changes to metabolism conspire to produce this differing outcome, however. Evidence to date suggests that increased autophagy is the primary mechanism by which reduced calorie intake produces benefits, but a full understanding remains to be achieved despite decades of research.

The altered metabolic state produced by calorie restriction is triggered by sensors detecting the availability of specific dietary components, such as the essential amino acid methionine. It is possible to create some fraction of the benefits of calorie restriction with a low methionine diet. Similarly, experiments have demonstrated that a reduced intake of various other amino acids can also produce some degree of benefits similar to those resulting from calorie restriction. Human trials of mild degrees of calorie restriction have been conducted, and analysis of that data continues years after the trials completed. There has been little comparable work on human trials of amino acid restriction, however.

Amino acid restriction, aging, and longevity: an update

Ever since the discovery that restricting laboratory rodent food consumption relative to their ad libitum (henceforth ad lib) feeding amount reliably extended their lives, prevented or delayed a host of diseases, and generally enhanced later life health, researchers have been seeking to discover the mechanisms by which such restriction works. One way to investigate this question is to determine whether a key feature of what we call the dietary restriction (DR) effect, that is, improved health, reduced disease, and extended longevity due to diminished food consumption, is to restrict various components of the diet as contrasted with simply reducing food consumption itself. By now, experimental reduction of all dietary macronutrients has been performed many times in addition to macronutrient components, particularly essential amino acids, in multiple species. Various diets, from low calorie to low protein to low methionine, branched-chain amino acids (BCAAs), or isoleucine formulations, have shown that dietary modulation can affect later life health in laboratory species. Whether these dietary enhancements of later life health will be translatable to humans is a question begging to be answered.

So far surveys of humans on plant-based low methionine or low sulfur amino acid (methionine + cysteine) diets have been reported to be associated with several beneficial health outcomes such as lower cardiometabolic risk factors or diabetes-related mortality. Short-term (4-12 weeks) clinical trials indicate that low sulfur amino acid diets as in most animal studies lead to weight loss, lower total cholesterol and LDL cholesterol, and other salubrious changes. The cancer field has been particularly interested in low methionine diets as both cell-based and preclinical studies confirm that cancer cells hunger for methionine. Yet short-term trials of medical methionine restriction, especially when combined other cancer therapies, have been generally less than successful largely because of low palatability of the diet. Clearly if low methionine or low sulfur amino acid diets are to be sustainable, the plant-based approach is more likely to be successful.

It is time to determine in human studies whether these low these amino acid restricting diets unlike chronic DR, are sustainable over the long-term and what the long-term health consequences might be. It is also important to discover how the diets affect mood, energy, and interact with other healthy-enhancing lifestyle or pharmaceutical interventions such as exercise or geroprotective drugs. We have reached the "translation stage" of biological aging research. It will be curious to see how successful that translation will be.

Klotho is a longevity-associated protein. Studies in mice show that upregulation lengthens life, while downregulation shortens life. In humans, levels of the soluble circulating form of α-klotho correlate with many aspects of aging. More of it is better, less of it is worse. Here, researchers show this to be the case for inflammation related to osteoarthritis. Identification of the full panoply of mechanisms by which klotho acts to improve health remains a work in progress. It is predominantly active in the kidney, and is clearly protective of kidney health and function in later life. Kidney function is important to the rest of the body, and this may be enough to explain much of the effect on health, inflammation, life span, and so forth. Circulating α-klotho appears to have effects on the brain, however, improving cognitive function even in younger animals. It may be that it has meaningful effects on other organs as well.

The systemic immune-inflammation index (SII) is an indicator of neutrophil, lymphocyte, and platelet counts that is used to evaluate inflammation, and it can more objectively reflect changes in the level of inflammation in the body. The SII can be calculated through routine blood examination, which has the advantages of speed, efficiency, simplicity, and low cost. Previous studies have confirmed that the SII has good clinical value in diagnosing chronic diseases such as tumours, osteoporosis, kidney stones, and rheumatoid arthritis.

The Klotho gene (also known as the longevity gene) is related to ageing and is believed to exert antiaging effects through various biological mechanisms. With the increase in academic research on the Klotho gene, the function of the Klotho gene has gradually been elucidated. Previous studies have shown that the Klotho gene plays a key biological role in antioxidant, anti-inflammatory, and antiapoptotic mechanisms; kidney protection; and the improvement of calcium metabolism and phosphorus metabolism.

The association between the SII and serum Klotho has not yet been revealed. To fill this gap, we used data from the National Health and Nutrition Examination Survey (NHANES) database in the United States to explore the relationship between the SII and serum Klotho concentrations in osteoarthritis (OA) patients. This study revealed a significant negative linear relationship between the SII and serum Klotho concentration in OA patients, indicating that a higher SII is associated with lower Klotho concentration. The SII can serve as a predictive indicator of serum Klotho concentrations in OA patients, and Klotho may serve as a potential anti-inflammatory drug for OA treatment. The causal relationship between the SII and serum Klotho concentration still needs further prospective cohort studies or Mendelian randomised studies for verification.

Link: https://doi.org/10.1371/journal.pone.0300674

Oxidative stress is the presence of a damaging level of oxidative molecules, more than cells can cope with without resulting in harmfully altered behavior, dysfunction, cell death, and so forth. Increased levels of oxidative molecules is a feature of aging and inflamed tissue. As researchers here note, it appears in the context of degenerative disc disease. Targeting oxidative stress with antioxidant compounds has achieved some success for some conditions of local inflammation, such as the use of mitochondrially targeted antioxidants for uveitis, but the fine details of how a specific antioxidant interacts with cellular machinery matters greatly. A range of antioxidants have been tested in animal models for the treatment of degenerative disc disease, but little of this has progressed into human trials.

Intervertebral disc degeneration (IDD) is caused by aging, long-term sitting, long-term spinal load, and other factors. At the same time smoking, diet, and other factors can also lead to IDD. Abnormal accumulation of reactive oxygen species (ROS) occurs within the intervertebral disc, causing the production-clearance homeostasis to be disrupted, and excess ROS leads to activation of pathways downstream of ROS, which in turn triggers a range of symptoms.

When IDD occurs, the disc system undergoes intense, localized oxidative stress. From a molecular perspective, superoxide dismutase activity is significantly reduced in the plasma of IDD patients or rats, and levels of various biomarkers of oxidative stress, including phospholipase A, fructosamine, malondialdehyde, peroxide potential, total hydrogen peroxide, advanced oxidation protein products and NO, induce DNA damage, lipid metabolism, and protein synthesis disorder. From the cellular perspective, oxidative stress promotes the degeneration of normal nucleus pulposus cells in the IVD microenvironment, and impedes the function of collagen-secreting cells.

From a more macroscopic point of view, the degeneration of nucleus pulposus cells results in the decrease of type II collagen content, which is replaced by type I collagen. The annulus fibrosus is impacted by external force, and its effect of dispersing and relieving stress is weakened, which makes the annulus fibrosus easier to break, and causes the nucleus pulposus to expand and compress the nerve, resulting in more clinical symptoms.

Link: https://doi.org/10.1016/j.arr.2024.102323

Today's open access review paper goes back to the basics on aging and cancer, a first principles consideration of whether or not the evidence shows that we should think of cancer as a distinct process from aging. It is certainly the case that while cancer incidence increases with age, it doesn't keep on increasing ad infinitum. In very late life, 90 and older, those who are not already dead from one cause or another actually have lower rates of cancer than younger cohorts. This may not be a only matter of those most prone to cancer having died already, but also reflect something fundamental about the way in which cellular biochemistry changes at that age.

The majority of cancer risk scales with age-related disability of the immune system, and with a growing burden of mutational damage that spreads through tissue. That growing mutational damage enables the catastrophic final change to produce runaway cancerous replication, while immune aging prevents this first cancerous cells from being caught and destroyed by immune cells. One of the primary goals of the immune system is to destroy potentially cancerous cells, but growing levels of chronic inflammation, tissue damage, and cell dysfunction prevent that from happening efficiently in later life. Cancers that predominantly occur in children are a strange exception, not the rule.

Why does cancer risk start to drop at a very old age? Plausibly because cell activity diminishes across the board; less activity means less chance of mutational damage and the creation of a cancerous cells. These are overly simplistic summaries of a much more complex reality, but they are starting points for thinking about cancer and aging.

Aging and cancer

Aging is the most important risk factor of malignant disease, the prevalence of which dramatically increases as adults age, reaching a peak around 85 or 90 years, when the incidence of new cancer diagnoses starts to decline and that of cardiovascular and other diseases ramps up. Aging is, to some degree, modulable, meaning that chronological age (measured in years) and biological age (measured by biological tests and clinical status) can be uncoupled from each other. A young biological age is linked to a reduced risk of malignant disease. For this reason, it may even be argued - in a polemic fashion - that aging is a modifiable risk factor of cancer. This speculation is apparently supported by epidemiological data indicating that lifestyle factors that slow the aging process - such as leanness, an equilibrated mostly plant-based diet, voluntary physical activity and the avoidance of environmental mutagens - also reduce the probability to develop malignant disease. This observation suggests - but does not prove - that aging and cancer share common causes that are influenced by lifestyle or, in a slightly different vision, that manifest aging precipitates the development of clinically detectable tumors that then develop as 'age-related diseases'.

In this review, we will examine the mechanistic connections between aging and malignant disease. We will first discuss arguments in favor of the null hypothesis, namely, that aging and cancer just coincide as we become older because both are time-dependent processes but do not necessarily share a common biological basis. This null hypothesis would be in line with the existence of childhood cancers and progeroid (i.e., aging-accelerating) syndromes that do not increase the likelihood to develop cancer. We will then examine the likely more broadly applicable hypothesis that aging and cancer have common mechanistic grounds, as supported by the idea that both these processes share molecular and cellular characteristics that have been referred to as 'meta-hallmarks' or 'agonistic hallmarks'. However, this hypothesis does not explain why very old age (older than 90 years) is accompanied by a reduction of the incidence of cancers, perhaps because certain 'antagonistic hallmarks' of aging counteract carcinogenesis.

We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.

An aneurysm is a weakened section of a major blood vessel wall that expands and remodels into a dilated bulge, vulnerable to rupture and subsequent death. Given that treatment often fails, prevention is of great interest to the research community. What are the contributing factors to the development of an aneurysm? Researchers here look at the contribution of inflammatory signaling, generally agreed upon to be central to the dysregulation of blood vessel tissue that leads to the creation of an aneurysm.

Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years, and it is characterized by the progressive pathological dilatation of the abdominal aortic wall. Most patients who develop AAA are usually asymptomatic; however, when the aneurysm expands and ruptures, its mortality is extremely high. According to reports, even if ruptured AAAs are treated in time, the cases fatality rate is still as high as 50-70%, coupled with the cases without timely surgery, the ruptured AAAs' total mortality can be as high as 90%.

Modern studies have identified aortic extracellular matrix (ECM) degradation, the apoptosis of vascular smooth muscle cells (VSMCs), and vascular chronic inflammatory response as the three basic pathological processes in the pathogenesis of AAA. Of these, vascular chronic inflammatory response is the core process. The cytokines released by inflammatory cells not only exacerbate ECM degradation but also lead to the apoptosis of VSMCs. For example, interleukin (IL)-1β, IL-6, IL-33, and other stimuli prompt macrophages or VSMCs to secrete matrix metalloproteinases (MMPs) that degrade elastin and collagen, leading to the apoptosis of VSMCs and ECM degradation, thereby disrupting the stability of the aortic wall architecture.

It has been demonstrated in animal experiments that the use of an IL-1β receptor inhibitor (anakinra) can effectively inhibit mouse AAA formation induced by porcine pancreatic elastase (PPE) perfusion. Therefore, inflammasome regulation of the secretion of cytokines like IL-1β and IL-18 may significantly influence AAA progression, which has been recognized as a chronic inflammatory disease. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods.

Link: https://doi.org/10.3390/ijms25095001

The progression of Alzheimer's disease varies considerably between patients. Is this a matter of random chance in the complex dysfunction of a complex system, or should researchers be looking more closely at genetic and epigenetic differences between patients as a contributing cause of this variability? Researchers here argue for this conclusion based on what is presently known of the heritability of Alzheimer's disease risk and specific genetic variants that are correlated with Alzheimer's disease risk.

Alzheimer's disease (AD) has traditionally been considered first and foremost a neurodegenerative condition. This neuron-centric view of AD is not wholly unjustified, as synapse and neuronal loss are cornerstone features of the worsening cognitive outcomes associated with disease progression.In addition, two primary histopathological hallmarks, extracellular β-amyloid deposition and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein, have informed much of the research on AD pathogenesis and are still fundamental scoring criteria of present molecular attempts to stage disease trajectory. However, we now know that the disease is more multifaceted than this, comprising different cell types, inflammatory overloads, the vasculature, and uniquely vulnerable brain regions, among others. Therefore, the limited success of AD therapies, which have focused largely on mitigating β-amyloid pathology, may stem from our inability to tackle the complexity of the disease and the heterogenicity of those suffering from it.

The genome holds the key to many of these individual differences. Genetics account for up to 58%-79% of AD risk, and about 75 susceptibility loci have been discovered to date. For comparison, the genetic component of Parkinson's disease is about 15%. In fact, the heritability of AD is so great that parental disease history has been employed to identify AD-by-proxy cases in attempts to increase the power of genetic association studies. Still, it has not been trivial to translate these genetic links into mechanistic breakthroughs and therapeutic targets, as the resulting functional outcomes and causal genes linked to each polymorphism remain mostly unresolved.

Here, we explore how genomic research has advanced the understanding of late-onset AD. This is, for us, the first meaning of the "broken" AD genome, akin to unraveling a code. But various processes centered on our DNA become dysfunctional in AD, imparting an equally significant connotation to the term; i.e., "broken" in this context alludes to the genome as a driver of disease. We primarily highlight findings originating from human datasets, as existing disease models often fail to recapitulate the full pathological spectrum of AD. We recognize the importance of these tools and, when appropriate, reference insights obtained using them. We also identify challenges for the field and discuss strategies for amassing the wealth of genomic information now available for developing therapeutics and clinical tools.

Link: https://doi.org/10.1016/j.xgen.2024.100555

Macrophages are innate immune cells of the body, microglia the analogous innate immune cells of the central nervous system. All microglia and most macrophages depend on the function of colony stimulating factor 1 receptor (CSF1R); if this protein or its function are suppressed, the cells die. Following clearance of microglia and macrophages, the populations are restored within a few weeks. If this is carried out in an old animal, the new microglia and macrophages lack some of problems exhibited by the prior population, such as excessive inflammatory signaling, a high burden of cellular senescence, and so forth. There are well established CSF1R inhibitor drugs, such as pexidartinib (PLX3397), and so one can find a number of studies in which neurodegenerative conditions associated with microglial inflammation are improved by temporary clearance followed by repopulation.

Today's open access paper is an example of this sort of work. The authors provide evidence for clearance of microglia to improve the environment of a damaged retina in a mouse model of age-related macular degeneration. One might compare this to past animal studies in which clearance of microglia improves Alzheimer's disease and reduces injury following stroke. Beyond that, a considerable weight of evidence links increased numbers of pro-inflammatory microglia, whether activated or senescent, to the onset and progression of neurodegenerative conditions. It is plausible that short-term treatment with pexidartinib or a similar CSF1R inhibitor, avoiding most of the side-effects that accompany long-term use in cancer patients, will prove to be beneficial enough to enter widespread use.

Microglial repopulation restricts ocular inflammation and choroidal neovascularization in mice

Age-related macular degeneration (AMD) is a prevalent, chronic and progressive retinal degenerative disease characterized by an inflammatory response mediated by activated microglia accumulating in the retina. While robust evidence clearly identifies the beneficial effects of microglial repopulation in degenerative neurological diseases, the contributions of repopulating microglia in the retinal degenerative diseases AMD and the potential mechanisms remain incompletely understood.

In this study, we demonstrated that ten days of the CSF1R inhibitor PLX3397 treatment to induce microglial repopulation exacerbated neovascular leakage and angiogenesis formation. We also found that the accumulation of senescent cells in laser sites and treatment with microglial repopulation increased microglial phagocytosis and led to reduced cellular senescence. In addition, new microglia produced less CXCL2 and exhibited lower levels of activation markers than resident microglia, thereby ameliorating leukocyte infiltration and attenuating the inflammatory response in choroidal neovascularization lesions. Our study provides promising insights into the potential of microglial repopulation as a novel, promising therapeutic approach for the treatment of AMD using a mouse model of laser-induced CNV.

Microglia have been implicated to accumulate in the subretinal space, subsequently switching into an activated phenotype and undergoing significant changes in their function in both AMD patients and mouse models. These activated microglia cause the excessive release of inflammatory mediators and a prolonged inflammatory response, which may result in the growth of neovascular lesions and further tissue damage. As microglial survival and function are critically dependent upon CSF1R, CSF1R inhibition can effectively deplete microglia. Withdrawal of CSF1R inhibition results in the rapid repopulation of the whole retina with naïve microglia. Now that microglial activation in CNV has been identified as a symptom of inflammatory damage which in turn exacerbates retinal degeneration, it is plausible to hypothesize that the replacement of these overactivated microglia with new microglia resembling nonreactive homeostatic microglia may relieve the inflammatory response and promote retinal tissue repair in AMD.

Researchers here argue for neural stem cells in the hypothalamus to support a youthful environment in many other tissues via secreted factors carried into circulation in exosomes. To the degree that this signaling falters with age, it contributes to the burden of aging and age-related dysfunction - though as ever it is challenging to assign a relative importance to this mechanism versus all of the others identified to date, or a firm place in a network of cause and consequence. I don't think that describing either the signaling or its reduction with age as a program is helpful. We might expect component parts of a complex system to evolve a dependency on the behavior of other component parts. There are any number of well-established examples of the interdependence of internal organ function in the aging body. This is just the way things work.

In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored.

Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes.

Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.

Link: https://doi.org/10.3390/ijms25105467

Popular science articles covering the longevity industry and research into the treatment of aging tend to be a grab-bag of different projects and people of wildly different value and characteristics, all given much the same weight in the narrative. It takes a year or two of work to come to some initial understanding of the state of the field of aging research, to be able to start to distinguish good ideas from bad ideas, and make arguments about what is likely to have larger versus smaller effects on aging. No popular science journalist has put in that time. If looking for a single point of blame, it may be that there is at present no agreed-upon way to measure efficacy of a treatment for aging in humans, coupled to the point that most approaches to slow aging via metabolic adjustment behave quite differently in long lived species (such as our own) versus short-lived species (such as laboratory mice). Absent a way to rapidly assess a treatment for aging in humans, people can continue to equate likely good and likely bad approaches without being called on it.

Longevity research is advancing - but slowly. Clinical trials are moving forward on select uses for longevity drugs, younger researchers are taking the field more seriously, and private organizations are pledging significant support to research: The Saudi-based Hevolution Foundation has promised up to $1 billion in funding annually for biotech startups and academic researchers.

But while there likely remain many promising treatment candidates that have yet to be identified, they would take decades to reach clinical trials. Even academics who are bullish on the promise of longevity research fear that, for all the fanfare, the field has become too fixated on a few drugs and lifestyle adjustments that have been under investigation for years, while neglecting the basic research that could reveal novel pathways to slow down human aging.

In the last two decades, scientists have performed hundreds of lab experiments - mostly on animals - on drugs like rapamycin, canagliflozin, acarbose, empagliflozin, metformin, and on interventions like calorie restriction in diets and removal of nondividing senescent cells. Instead of testing the effects of these treatments on specific illnesses, many of these studies test whether certain interventions slow down animals' aging processes and help them live longer.

The expansion of longevity research has unearthed some potentially useful information about which biological mechanisms control aging and how to alter them. In mice and other species, changing a single pathway has the power to extend life by significant margins, raising hopes that if humans respond similarly, certain drugs could extend human lives by years. The horizon for this future is still far off. Most researchers I spoke to didn't believe that humans were going to experience a rapid increase in life expectancy any time soon - or maybe ever. They believed progress would instead be made in healthspan, helping people stay healthier for longer and avoiding long periods of physical and cognitive decline as they get older.

Link: https://www.vox.com/the-highlight/24121932/anti-aging-longevity-science-health-drugs