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- Lifestyle Choices Do Slow Aging, Just Not as Much as We'd Like
- The Slow Spread of Off-Label Use for Treatments Shown to Target Mechanisms of Aging
- Cardiovascular Aging Correlates with Brain Aging
- Endothelial Cell Senescence in Atherosclerosis
- What Can Be Learned About Energy Metabolism and Longevity from Birds?
- Amyloid Aggregation in the Brain as a Driver of White Matter Hyperintensities
- TREM2 in the Development of Atherosclerosis
- Considering the Non-Genomic Hallmarks of Aging
- Biological Age Acceleration Correlates with Increased Risk of Dementia and Stroke
- Assessing Phenotypic Age Acceleration Differences by Lifestyle Choice
- A Path to Increasing Glutathione Levels in Mitochondria
- Can Removing Amyloid Early Benefit Alzheimer's Disease Patients?
- Icariin is Neuroprotective, Reducing Ferroptosis
- Particulate Air Pollution and Its Effects on the Mechanisms of Degenerative Aging
- The Brain Microbiome Theory of Alzheimer's Disease
Lifestyle Choices Do Slow Aging, Just Not as Much as We'd Like
In recent years, a number of epidemiological studies have demonstrated that people with healthier lifestyles tend to live longer, at least within the bounds of later life from 60 to 100. That in turn is reflected by a lesser burden of various forms of cell and tissue damage, such as the accumulation of senescent cells. This isn't a controversial statement, though there is room enough to argue for an eternity over just how large the effect of any specific choice might be, how that effect size varies between populations, how different choices combine, and so forth. Then on top of all of this, the question of what happens and why in extreme old age past 100 exists in its own realm of comparatively little data because of the low survival to such advanced ages.
Arguably we shouldn't much care about centenarians and the fine details of the various lifestyle and biological contributions to their survival odds, as it is much akin to asking why some people managed to die more slowly when infected with tuberculosis prior to the development of effective antibiotics. That question isn't the right focus for the problem. The right focus for aging is on the common root cause mechanisms that conspire to kill everyone, and on reversing those mechanisms such that no-one is killed by them. Understanding how some people manage to resist the cell and tissue damage of aging for a longer rather than a shorter span of years is irrelevant in comparison to understanding how to repair that damage.
The first rejuvenation therapies, in the form of first generation senolytics such as the dasatinib and quercetin combination, exist, are available to the adventurous, and are taking a surprisingly long time to emerge into a wider appreciation of their potential. The rest of the package of biotechnologies needed for human rejuvenation are going to take an appreciable amount of time to arrive in the clinic, perhaps several decades at this point, barring a major shift in the way in which medical regulation works. So if one can add a few years by making smarter lifestyle choices, then why not? It isn't any big secret as to what those choices are: regular exercise, strength training, calorie restriction of some form, and avoiding the many forms of readily available self-sabotage such as smoking.
Lifestyle interventions to delay senescence
Senescence is a condition of cell cycle arrest that increases inflammation and contributes to the development of chronic diseases in the aging human body. The beneficial role of senescent cells early in life can become detrimental in later years. The accumulation of senescent cells with time reduces the capacity of the body to regenerate and induces chronic inflammation via the senescence-associated secretory phenotype (SASP), which contributes to the condition of inflammaging during the aging process and especially in older adults. While senotherapies capable of clearing senescent cells have emerged as potential treatments for chronic diseases, less attention has been devoted to the effects of lifestyle interventions that are widely available, easy to implement, and safe when used as recommended.
Exercise is widely recognized to produce beneficial effects on health of animals and humans. Several preclinical studies indicate that exercise can reduce the number of senescent cells in various organs including the heart, liver, muscles, kidneys, and adipose tissues. For instance, wheel running for three weeks reduced the senescence marker p16 in the heart of mice. Aerobic treadmill exercise for 15-60 minutes daily, five times per week for six weeks reduced levels of senescence-associated beta-galactosidase in the kidneys of aged mice. Similarly, a three-month swimming program reduced senescence markers and the pro-inflammatory cytokine interleukin-6 (IL-6) in the liver of rodents treated with d-galactose to induce aging. However, the high heterogeneity of exercise regimens used in these animal models and the sole reliance on senescence markers limit our understanding of the mechanisms underlying the effects of exercise on senescence.
In humans, regular physical activity for at least 4 hours per month is associated with reduced levels of p16INK4 in T lymphocytes. A five-month training program reduced the number of p16INK4-positive senescent cells in thigh adipose tissues of older overweight women. Expression of p16 and IL-6 was elevated in the colonic mucosa of middle-aged and older overweight men compared to young sedentary men, whereas this elevation was blunted in age-matched endurance runners with several years of experience. Similarly, the increase of senescent endothelial cells and impaired vascular endothelial function that is observed in brachial arteries of older sedentary individuals was absent in older exercising subjects.
Different lifestyle interventions including exercise, nutrition, intermittent fasting, and consumption of phytochemicals, prebiotics and probiotics, and adequate sleep can produce anti-senescence effects in model organisms and humans. Given the widespread beneficial effects of these lifestyle interventions, the findings described here are perhaps not surprising - except that the reduction of senescent cells represents a new mechanism of action to explain the effects of these interventions. The effects of lifestyle factors on senescence are quite complex and can easily be neutralized or become detrimental depending on their intensity and frequency. Moreover, an unhealthy lifestyle involving sedentarity, consumption of excess alcohol, smoking, lack of sleep and sunlight exposure and chronic stress may offset some of the beneficial effects of other interventions on senescence. More attention should therefore be given to the modalities that produce beneficial effects and their interactions with anti-senescence compounds and other lifestyle habits.
The Slow Spread of Off-Label Use for Treatments Shown to Target Mechanisms of Aging
A small number of low-cost and generic drugs have extensive human use and safety data, but also a sizable, compelling body of animal study evidence to either (a) suggest a likely modest slowing of aging, e.g. rapamycin, or (b) demonstrate the ability to target a mechanism of aging to reverse age-related disease, e.g. the dasatinib and quercetin combination, shown to selectively destroy senescent cells. In the US any drug approved for a given use can also be used off-label to treat other conditions. In principle the drug can be prescribed by any physician in this way. This is legal, though tends to require a slow bootstrapping process of education, physician acceptance, gradual gathering of more data for the intended off-label use, and eventual grandstanding and interference by regulators.
It is an important process, though. Not just because it is a path to what are likely significant gains to health for the older end of the population, and not just because it is the only viable way to produce clinical data for generic drugs, as there is no financial incentive for industry to fund clinical trials of these treatments, but also because adoption drives public support for greater funding of research into treating aging as a medical condition, and greater investment in the longevity industry. At present, funding for aging research is a tiny anemic fraction of expenditure on medicine, and the longevity industry is minuscule compared to the broader biotech and medical industry. This is a ridiculous state of affairs given the staggering human and economic costs of aging, the vast and ongoing death toll, the hundreds of millions crippled by degenerative disease.
Philanthropists can play a role in speeding up the evaluation and adoption of low cost treatments like rapamycin and dasatinib and quercetin. Rather than leaving the present slow bootstrapping to run its course, a process that could easily consume another decade or two, matters can be accelerated by organizing informal but well-run trials in a few hundred individuals. The cost of this can be 500,000 to 1,000,000 or so per trial, we within the reach of many longevity-interested philanthropists. As a model, look at the PEARL trial crowdfunded by Lifespan.io, an example of how to do something meaningful in this space at a comparatively small expense. Such trials can be followed up with outreach to physician networks and patient advocacy groups, increasing the number of physicians willing to prescribe these treatments off-label. This would be a worthy exercise.
Is the Secret to a Longer Life Already Available at Your Local Pharmacy?
Depending on who you ask, we may be on the cusp of a great leap forward in longevity medicine. "In probably the next three to four years, you will have this pill basket" of anti-aging drugs. Based on the patient's health profile, a clinician could tap into the basket's selections and prescribe something to improve health during their final decades: "Let us see whether we can add 10 more years of a healthy life to you." You'd have to be remarkably bullish to believe those drugs will prove to greatly boost the quality and length of late life in the imminent future. There are doubts that the potential of these therapies will be fully understood - and thus implemented most effectively - any time soon. After all, proper testing would take decades. Yet some experts in the burgeoning field of geroscience are increasingly confident that a batch of different molecules undergoing analysis for anti-aging properties contains game-changers. Among the potential prize ponies are prescription drugs like rapamycin, metformin, and senolytics, alongside supplements like alpha-ketoglutarate and taurine. The aim is to perfect an array of molecules that not only extend the life expectancy of users, but also boost overall health during their final years.
But despite the potentially transformative nature of these molecules, some spectators have found progress to be needlessly slow. "The way our regulatory system is structured, there's just no incentive to do those trials." Because many of the promising candidates are already generic drugs, the rate of research has been gradual. Without serious money to make, even the prospect of a non-metaphorical Holy Grail can't motivate the pharmaceutical industry. The structure of FDA trials are also an awkward fit with geroscience. When testing the efficacy of an anti-aging therapy, what do you measure? There's not a catch-all biomarker. "If we go to the FDA with a blood pressure medication, we measure blood pressure to know if the drug is working or not. With aging, it's really hard to go with what marker you're going to use."
Nonetheless, progress has continued. Closely watching the advance are so-called biohacker communities, online groups that digest any new data to guide their own regimens of potential longevity drugs-typically therapies for other illnesses taken off-label - hoping for a headstart on treatments whose effectiveness will later be fully proven. The search for life-lengtheners has long attracted bunk science and charlatans, and the addition of outsider research - legitimate or not - could give medical experts pause. "That's something that the aging community is really wrestling with right now. Aging has really been pushed to the forefront, which is a good thing. But we're trying to get past the pseudoscience of the Fountain of Youth and that kind of thing."
But even as that tension persists, amateur discourse around these drugs may have the effect of drawing the attention of physicians. A primary feature of digital communities devoted to gerontology is to share where certain therapies may be procured. It provides not just an access point for future users, but it could also serve to reassure prospective prescribers. "There's a small group of them at first. But once they see some of their colleagues doing this - and maybe their colleagues have 100 or 500 patients on rapamycin - then they start to feel comfortable." Thus, as the online community of people allegedly taking these drugs grows, its relationship with the medical community becomes more reciprocal, and a given drug's credibility "percolates through the medical community that way."
Cardiovascular Aging Correlates with Brain Aging
Many large epidemiological studies demonstrate a correlation between cardiovascular aging and the risk of suffering cognitive decline and dementia. The population size of such studies has increased in recent years with the advent of sizable national databases, such as the UK Biobank. Today's open access paper focuses on one specific aspect of cardiovascular aging, the onset of atrial fibrillation, irregular heartbeats that can be accompanied by palpitations and other worrying sensations. Atrial fibrillation can arise in combination with many of the features of cardiovascular aging, and one might argue that data on time of diagnosis is interesting because the physical sensation of atrial fibrillation might more readily drive people to see a physician (and thus become a row in a database) than is the case for other early manifestations of declining heart function.
Regardless of that speculation, the researchers demonstrated that earlier diagnosis of atrial fibrillation, indicative in some fraction of cases that other cardiovascular issues are present, is associated with increased risk of suffering later dementia. The brain is an energy-hungry organ, and cardiovascular aging can imply reduced blood flow to the brain, a lower supply of nutrients that has consequences over the long term. That cardiovascular aging associated is typically also accompanied by a greater decline in quality of blood vessels and higher blood pressure, leading to damage and rupture of small vessels in the brain. There are numerous other mechanisms that likely contribute meaningfully to the link between heart, circulation, and brain, of course: nothing is ever simple in the biology of aging.
Age at Diagnosis of Atrial Fibrillation and Incident Dementia
To examine whether age at atrial fibrillation (AF) diagnosis is associated with risk of incident dementia and its subtypes, this prospective, population-based cohort study used data from UK Biobank, a public, open-access database in the UK with baseline information collected from 2006 to 2010. A total of 433,746 participants were included in the main analysis after excluding participants with a diagnosis of dementia or AF at baseline, missing data on covariates, or having dementia before AF onset during a median follow-up of 12.6 years. Data were analyzed from October to December 2022.
Our research showed that AF participants had an elevated risk of subsequent dementia compared with participants without AF. More importantly, multivariate Cox regression models indicated that an earlier diagnosis of AF was associated with greater risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD). Additionally, the results remained robust after propensity score matching, reinforcing the fact that the probability of developing dementia increases with a younger onset age of AF.
Compared with individuals without AF, 30,601 individuals with AF had a higher risk of developing all-cause dementia (adjusted hazard ratio [HR], 1.42). Among participants with AF, younger age at AF onset was associated with higher risks of developing all-cause dementia (adjusted HR per 10-year decrease, 1.23), AD (adjusted HR per 10-year decrease, 1.27), and VD (adjusted HR per 10-year decrease, 1.35). After propensity score matching, individuals with AF diagnosed before age 65 years had the highest HR of developing all-cause dementia (adjusted HR, 1.82), followed by AF diagnosed at age 65 to 74 years (adjusted HR, 1.47) and diagnosed at age 75 years or older (adjusted HR, 1.11). Similar results can be seen in AD and VD.
To our knowledge, while current epidemiological studies still focus predominantly on the association between AF and subsequent cognitive decline or incident dementia, the present study is the largest study to explore the association between AF onset age and incident dementia. Based on accurate data on AF diagnoses and incident dementia, the most distinguished finding of our research was that an earlier diagnosis of AF was associated with an elevated risk of developing all-cause dementia, AD, and VD.
Endothelial Cell Senescence in Atherosclerosis
Senescent cells accumulate throughout the body with age. They are created constantly due to stresses placed upon cells, and when somatic cells reach the Hayflick limit on replication, and are cleared by the immune system. This process of clearance slows down with age, unfortunately, and so a burden of lingering senescent cells begins to build up. Senescent cells are disruptive to tissue structure and function, even when present in comparatively small numbers relative to other cells in a tissue, as a result of the pro-growth, pro-inflammatory signals that they generate.
Atherosclerosis involves the generation of fatty lesions that narrow and weaken blood vessels, and is the leading cause of human mortality, as rupture of these lesions causes stroke and heart attack. We might view it as a condition of macrophage dysfunction, as these are the cells tasked with cleaning up the excess cholesterol and cell debris that form the bulk of an atherosclerotic lesion. The lesions grow to the degree that macrophages become overwhelmed and begin to die, calling for more support as they do so. In this context, to what degree is atherosclerosis driven by cellular senescence? And which sort of senescent cells?
It is known that cells become senescent in and around atherosclerotic lesions, and that clearing them in animal models helps to slow progression of pathology; one can speculate on the mechanisms by which various types of senescent cell can contribute to make the lesion environment worse. Sadly, no-one has yet run clinical trials of the known senolytic drugs capable of clearing senescent cells in human patients. Nor are they likely too, given the high costs of such a trial, and the inability to profit from new data on existing drugs.
New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death
Atherosclerosis is a chronic cardiovascular disease (CVD) that poses significant risks to human health, and is the underlying cause of peripheral vascular disease, coronary heart disease, and stroke. The pathogenesis of atherosclerosis is complex and involves various cell types, including endothelial cells (ECs), vascular smooth muscle cells (SMCs), adventitial fibroblasts, macrophages, and other immune cells. Key factors in the development of atherosclerosis include endothelial dysfunction, leukocyte adhesion, foam macrophage formation, and SMC phenotypic transition.
Endothelial dysfunction is considered the initial step in atherosclerosis, and in its broadest sense, it encompasses a constellation of nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone, redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. ECs that line elastic arteries, such as the aorta, carotid artery, and femoral artery, have critical functions in maintaining vascular homeostasis. The primary function of the endothelium is to produce nitric oxide (NO) and other vasoactive substances to regulate vascular tone.
ECs form a continuous monolayer barrier that controls substance exchange among the lumen, vascular wall, and parenchyma. A specialized barrier function of the endothelium involves its immunoregulatory effects on leukocyte recruitment. Quiescent endothelium is immunosuppressive, with a surface glycoprotein profile that prevents leukocyte adhesion, crawling, and extravasation. Upon tissue injury and inflammatory stress, activated ECs present adhesive molecules, such as vascular cell adhesion molecule-1 (VCAM-1), to the cell surface to facilitate the transendothelial migration of leukocytes. The reactive, pro-inflammatory phenotype of ECs is indispensable for tissue repair after acute injury. However, in the context of chronic tissue damage, such as atherosclerosis, persistent endothelial inflammation becomes pathogenic. Moreover, the regenerative capacity of ECs is intrinsically critical to the re-endothelialization of the surface-eroded arterial lumen and the stabilization of atherosclerotic lesions. Notably, most of these endothelial dysfunctions are associated with endothelial cell senescence and death.
Cellular senescence is a process in which cells undergo permanent cell cycle arrest, with an altered secretome to remodel neighboring cells and the extracellular matrix (ECM) microenvironment. Notably, vascular aging in animal models and humans is characterized by impaired endothelium-dependent dilation (EDD), perturbed fibrinolysis, enhanced permeability, and aberrant angiogenesis. In humans, endothelium-dependent vasodilation, usually measured as flow-mediated dilation of the radial artery, serves as a non-invasive marker of vascular aging and cardiovascular damage, even in the absence of clinical symptoms. Importantly, cellular senescence of the endothelium is an integral component of vascular aging, as well as atherosclerosis. EC senescence triggers structural and functional deterioration of the vascular wall by not only deterring re-endothelialization and barrier reconstitution at the injury zone, but also promoting an inflammatory and thrombotic niche via the senescence secretome, thereby contributing to the development and progression of CVD.
What Can Be Learned About Energy Metabolism and Longevity from Birds?
Here find an interesting commentary on some of the evolved genetic differences between mammals and birds, with a focus on genes relevant to energy metabolism - and potentially to species longevity. Larger animals live longer, but birds tend to be long-lived for their size. This is also the case for some bat species. It is thought that adaptations to energy metabolism needed to support the very energy-intensive activity of flight are involved in this increased longevity, providing resilience as a side effect.
The details have yet to be mapped in any comprehensive way, but studies such as today's open access example are steps towards that goal. Energy metabolism is closely associated with mitochondrial function and oxidative stress, both of which appear strongly connected to processes of aging. Loss of mitochondrial function and rising oxidative stress are features of aging, but in the short term are also features of exertion. It is plausible to argue that systems that evolved to cope with and minimize the side effects of high energy expenditure seem likely to also increase longevity. It is perhaps interesting that this isn't universal, that we do still see comparatively short-lived birds and bats despite their capability of flight.
As with all such research, it is an open question as to whether there is anything to find that could form the basis for near-term therapies in humans. In the much longer term, rebuilding human biology from the ground up will certainly take place, incorporating everything learned from a study of comparative biology, and likely going beyond to the production of wholly artificial biological systems that are better yet, but those of us reading this now only have so much time on hand to await treatments capable of producing longer healthy life spans.
Gene purging and the evolution of Neoave metabolism and longevity
Aves emerged from bipedal dinosaurs ∼165-150 million years ago (MYA), survived the Cretaceous-Paleogene extinction event 66 MYA, and then diversified into the ∼10,000 Neoaves species we observed today. The benefits of becoming endothermic, smaller, and adapted for flapping-wing flight allowed for greater foraging opportunities, predator avoidance, and tolerance to a great range of environments. The power required to fly long distances is largely a multiple of basal metabolic rates (BMR), and smaller birds with proportionately more fat reserves can fly longer distances than large birds. Indeed, genes involved in energy metabolism show strong evidence of positive selection, suggesting early adaptative mutations required for flight. Body mass correlates with BMR and longevity, although shifts and variation across vertebrate phylogeny remain unexplained. Many Neoaves are outliers, showing greater longevity and higher BMR than expected relative to body size.
Maintenance of the proteasome requires oxidative phosphorylation to produce ATP and mitigation of oxidative damage, in an increasing dysfunctional relationship with aging. SLC3A2 plays a role on both sides of this dichotomy as an adaptor to SLC7A5, a transporter of branched-chain amino acids (BCAA), and to SLC7A11, a cystine importer supplying cysteine to the synthesis of the antioxidant glutathione. Endurance in mammalian muscle depends in part on oxidation of BCAA, however elevated serum levels are associated with insulin resistance and shortened lifespans. Intriguingly, the evolution of modern birds (Neoaves) has entailed the purging of genes including SLC3A2 and SLC7A5, largely removing BCAA exchangers in pursuit of improved energetics.
Additional gene purging included mitochondrial BCAA aminotransferase (BCAT2), pointing to reduced oxidation of BCAA and increased hepatic conversion to triglycerides and glucose. Fat deposits are anhydrous and highly reduced, maximizing the fuel/weight ratio for prolonged flight, but fat accumulation in muscle cells of aging humans contributes to inflammation, and senescence. Duplications of the bidirectional α-ketoacid transporters SLC16A3, SLC16A7, the cystine transporters SLC7A9, SLC7A11, and N-glycan branching enzymes MGAT4B, MGAT4C in Neoaves suggests a shift to the transport of deaminated essential amino acid, and stronger mitigation of oxidative stress supported by the galectin lattice.
Amyloid Aggregation in the Brain as a Driver of White Matter Hyperintensities
A white matter hyperintensity is a small areas of tissue damage in the brain, such as results from rupture of a small blood vessel and consequent bleeding. These areas of damage are readily visible in MRI scans, and their prevalence is known to correlate with loss of cognitive function and rising dementia risk. Here, researchers provide evidence to suggest that this process is primarily the result of amyloid-β aggregation in the brain rather than vascular aging processes.
Bright spots called white-matter hyperintensities (WMHs) often appear on MRI scans of people with familial or sporadic Alzheimer's disease (AD), and they tend to intensify as the disease progresses. Some scientists think they reflect cerebrovascular disease. However, researchers now offer a different explanation. They reported that WMHs worsened most in people with extensive neurodegeneration, amyloid plaques, or cerebral microbleeds, a sign of cerebral amyloid angiopathy (CAA), while WMH severity did not correlate with vascular risk. They concluded that WMHs are driven by AD pathology.
Researchers compared the total volume of WMHs to cardiovascular risk, as measured by the Framingham Heart Study cardiovascular disease risk score, and to the amount of amyloid, be it plaques or CAA. Researchers drew data from clinical records and almost 4,000 brain scans of 1,141 people from three longitudinal cohorts: the Harvard Aging Brain Study, the Alzheimer's Disease Neuroimaging Initiative, and the Dominantly Inherited Alzheimer Network. At baseline, WMH volume was greatest among those who were oldest, had the least gray matter, the highest amyloid burden, or who had two or more cerebral microbleeds, a commonly used indicator of CAA that can only be diagnosed at autopsy. Over time, WMHs worsened more among these people than among their respective controls.
This fits with the idea that amyloid constricts blood vessels. Researchers have found that soluble amyloid-β slowed cerebral blood flow in wild-type and amyloidosis mice and that vascular injury can be prevented if reactive oxygen species (ROS) scavengers are administered before the peptide settles into vessels as CAA. ROS are a major cause of vessel damage by amyloid-β. Did vascular health factor into WMH severity? Surprisingly, the amount of WMHs had no correlation with cardiovascular risk score after accounting for age, gray-matter volume, amyloid burden, and cerebral microbleeds. The authors concluded that amyloid and gray-matter atrophy, i.e., neurodegeneration, drives the brain lesions rather than small-vessel disease.
TREM2 in the Development of Atherosclerosis
TREM2 is most studied in the context of Alzheimer's disease and related forms of neurodegeneration, where it seems to affect inflammation driven by microglia and loss of the ability of microglia to clear amyloid-β from the aging brain. Microglia are, more or less, the central nervous system version of the innate immune cells called macrophages that are found throughout the rest of the body. Atherosclerosis is the largest cause of human mortality, and is driven by macrophage dysfunction. Macrophages are responsible for clearing excess lipids from blood vessel walls, but when these cells become overwhelmed by local excesses of lipids they become inflammatory, contributing to the growth of atherosclerotic plaques rather than helping the situation. As noted here, it appears that TREM2 is involved in this process, affecting the capacity of macrophages to resist the plaque environment.
Atherosclerosis is driven by the expansion of cholesterol-loaded 'foamy' macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment, or cholesterol levels.
Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.
Considering the Non-Genomic Hallmarks of Aging
The Hallmarks of Aging were first published some years ago now, long enough to be expanded upon and much debated. The hallmarks are a list of characteristic changes in cell and tissue biochemistry noted to take place with advancing age, some of which are likely causes of age-related degeneration, some of which are likely downstream consequences, and all of which interact with one another. As often happens in such matters, the original hallmarks of aging drew from, and then eclipsed in terms of attention, the much earlier Strategies for Engineered Negligible Senescence (SENS) list of forms of cell and tissue damage that are causative of aging. In this review paper, researchers provide an overview of the subset of the hallmarks of aging that are not directly connected to the genome.
Aging is defined as a process in which there is a gradual loss of organ function and a reduction in the ability to regenerate. This is due to the multiple changes that occur at the molecular and cellular levels. Various theories have been formulated to explain the cause of aging, e.g., oxidative damage or programmed theory. These theories cover only a certain aspect of the aging process and do not consider its full complexity. The theory that connects all causes of aging is based on the hallmarks of aging, molecular processes that accumulate damage during aging that exceed the cell's ability to repair it.
The most significant changes at the genomic level (DNA damage, telomere shortening, epigenetic changes) and non-genomic changes are referred to as hallmarks of aging. The hallmarks of aging and cancer are intertwined. Many studies have focused on genomic hallmarks, but non-genomic hallmarks are also important and may additionally cause genomic damage and increase the expression of genomic hallmarks. Understanding the non-genomic hallmarks of aging and cancer, and how they are intertwined, may lead to the development of approaches that could influence these hallmarks and thus function not only to slow aging but also to prevent cancer. In this review, we focus on non-genomic changes. We discuss cell senescence, disruption of proteostasis, deregualation of nutrient sensing, dysregulation of immune system function, intercellular communication, mitochondrial dysfunction, stem cell exhaustion, and dysbiosis.
Biological Age Acceleration Correlates with Increased Risk of Dementia and Stroke
There are now many ways to determine biological age, the most prevalent of which are epigenetic clocks and combinations of normal blood biomarkers such as the phenotypic age clock. In all cases, the idea is to identify specific measurable changes that correlate with age, and then develop an algorithm that combines the measures to produce an age as the output. Whether a given clock actually reflects all of the processes of aging, and what exactly is being measured under the hood, are questions that have yet to be satisfactorily answered. It has been noted that in all of the established biological age measures, people with a higher biological age than chronological age also exhibit a higher risk of age-related disease. This is the case here, for another novel measure of biological age that is derived from a combination of simple biomarkers.
In order to measure biological age and the link to disease, the researchers used data from the UK Biobank. They studied a cohort of 325,000 people who were all between 40 and 70 years old at the time of the first measurement. Biological age was calculated using 18 biomarkers, including blood lipids, blood sugar, blood pressure, lung function, and BMI. The researchers then investigated the relationship between these biomarkers and the risk of developing neurodegenerative diseases such as dementia, stroke, ALS, and Parkinson's disease within a nine-year period.
When compared to actual, chronological age, high biological age was linked to a significantly increased risk of dementia, especially vascular dementia, and ischemic stroke, (i.e. blood clot in the brain). "If a person's biological age is five years higher than their actual age, the person has a 40 per cent higher risk of developing vascular dementia or suffering a stroke." The results are particularly interesting because the study included such a large group of people. This makes it possible to break down the material into smaller pieces and capture less common diagnoses such as ALS. The risk of developing ALS also increases with higher biological age. However, no such risk increase was seen for Parkinson's disease.
Assessing Phenotypic Age Acceleration Differences by Lifestyle Choice
Phenotypic age is one of the less complicated biological age measures developed in recent years. As for all of the others, it was developed by using machine learning on a large set of human data, in this case commonly assessed blood biomarkers and their values at different ages. Thus while we know exactly what is being measured, it is an open question as to how those measurements relate to the underlying processes of aging, or indeed whether they accurately reflect all of those processes. Once one starts down the path of using lifestyle interventions to slow aging or novel therapies to repair the cell and tissue damage that causes aging, will phenotypic age usefully report the outcomes? Maybe it will, maybe it won't, and the answer may be different for every different type of intervention. The only way to be certain is to calibrate the biological age measure against actual outcomes, and the study noted here is a step in that direction.
Having high cardiovascular health may slow the pace of biological aging, which may reduce the risk of developing cardiovascular and other age-related diseases while extending life. Researchers examined the association between heart and brain health, as measured by the American Heart Association's Life's Essential 8 checklist and the biological aging process, as measured by phenotypic age.
Instead of a calendar to assess chronological (actual) age, phenotypic age is a robust measure of biological (physiological) age calculated based on your chronological age plus the results of nine blood markers (routinely captured during clinical visits) for metabolism, inflammation, and organ function (including glucose, C-reactive protein, and creatinine). Phenotypic age acceleration is the difference between one's phenotypic age and actual age. A higher phenotypic age acceleration value indicates faster biological aging.
After calculating phenotypic age and phenotypic age acceleration for more than 6,500 adults who participated in the 2015-2018 National Health and Nutrition Examination Survey (NHANES), the analysis found that participants with high cardiovascular health had a negative phenotypic age acceleration - meaning that they were younger than expected physiologically. In contrast, those with low cardiovascular health had a positive phenotypic age acceleration - meaning that they were older than expected physiologically. For example, the average actual age of those with high cardiovascular health was 41, yet their average biological age was 36; and the average actual age of those who had low cardiovascular health was 53, though their average biological age was 57.
After accounting for social, economic and demographic factors, having the highest Life's Essential 8 score (high cardiovascular health) was associated with having a biological age that is on average six years younger than the individual's actual age when compared to having the lowest score (low cardiovascular health).
A Path to Increasing Glutathione Levels in Mitochondria
Glutathione is an interesting cellular antioxidant, as increased levels can improve health in humans and slow aging in animal models. You might recall recent small human trials of high dose supplementation of glutathione precursors in order to achieve upregulation of glutathione, and corresponding studies in mice. It is thought that glutathione upregulation may largely improve health via mitochondrial function, as mitochondria are a prominent source of oxidative stress in aging cells. Here, researchers find a mechanism that regulates the amount of glutathione that enters the mitochondria, and thus a possible target to increase this level without the need for global upregulation. Whether not it is capable of producing greater benefits remains to be seen.
Glutathione is an antioxidant produced throughout the body that plays many important roles, including neutralizing unstable oxygen molecules called free radicals, which cause damage to DNA and cells if left unchecked. It also helps repair cellular damage and regulates cell proliferation, and its loss is associated with aging, neurodegeneration, and cancer. As a result, glutathione supplements have become increasingly popular as an over-the-counter approach to wellness. The antioxidant is especially abundant in mitochondria, which cannot function without it. As the respiratory organelle, mitochondria produces energy, but mitochondria can also the source of a lot of oxidative stress, implicated in cancer, diabetes, metabolic disorders, and heart and lung diseases, among others. If glutathione levels aren't precisely maintained in mitochondria, all systems fail. None of us can survive without it.
How glutathione actually enters mitochondria was unknown until 2021, when researchers discovered that a transporter protein called SLC25A39 delivers the package. It also appeared to regulate the amount of glutathione. "When the antioxidants are low, the level of SLC25A39 increases, and when the antioxidant levels are high, the transport level goes down. Somehow a mitochondrion figures out how much antioxidant it has, and depending on that amount, it regulates the amount of antioxidant it lets inside."
To ferret out how mitochondria do it, researchers used a combination of biochemical studies, computational methods, and genetic screens to discover that SLC25A39 is both a sensor and a transporter at the same time. It has two completely independent domains. One domain senses the glutathione, and the other transports it. Now that the researchers know how SLC25A39's package delivery system operates, they can experiment with manipulating it. "This particular transporter protein is upregulated in a group of cancers. People have tried to change overall glutathione levels, but now we have a way to change it in mitochondria without impacting other parts of the cell. This kind of targeted therapy could potentially lower the number of side effects that can come with altering glutathione levels across the whole body."
Can Removing Amyloid Early Benefit Alzheimer's Disease Patients?
The amyloid cascade hypothesis of Alzheimer's disease suggests that aggregation of misfolded amyloid-β sets the stage for a feedback loop between chronic inflammation of brain tissue and tau aggregation. It is that second step that causes severe pathology and death, and once it is underway in earnest a patient's amyloid-β burden is of little relevance. This the explanation given for the lack of patient benefits resulting from the successful clearance of amyloid-β using forms of immunotherapy. The industry has now shifted to testing these treatments in patients at an earlier stage of Alzheimer's disease, and there are preliminary signs that this might be producing results. Even so, it may still be the case that amyloid-β is only a sidebar to other, more important disease mechanisms. Some researchers argue for chronic inflammation, driven by factors such as persistent viral infection, to be the true cause, for example.
Some researchers have long argued for starting amyloid immunotherapy early, before neurofibrillary tangles spread and neurons die all over the brain. They have recently added flesh to the bone of this idea. Despite coming from different anti-amyloid antibody therapies - donanemab, lecanemab, gantenerumab - the findings paint a convergent picture. In short, participants at the earliest stages of the respective cohorts enrolled in each trial gained the most cognitively from treatment. The findings are preliminary, often involving post hoc analyses of small numbers of participants remaining from large trials.
In one striking tease, about two-thirds of participants with very early Alzheimer's disease who took lecanemab actually improved on the Clinical Dementia Rating Scale Sum of Boxes Scores (CDR-SB) over 18 months, compared with about one-third of a matched placebo group. Other findings offered the first concrete indication that amyloid immunotherapy may be able to prevent Alzheimer's disease. In the Dominantly Inherited Alzheimer Network secondary prevention trial, presymptomatic mutation carriers taking gantenerumab for eight years had half the odds of developing symptoms as did those on placebo.
Icariin is Neuroprotective, Reducing Ferroptosis
In animal studies, icariin has been shown to favorably change the balance of microbial populations in the aging gut microbiome, and is modestly protective against a range of age-related declines. How exactly it operates remains to be seen, but given that it alters the gut microbiome, there are likely many relevant mechanisms that stem from the influence of the microbiome on cell function through the body. Researchers here note that icariin reduces a form of programmed cell death in the aged brain, a contributing cause of neurodegeneration.
Icariin (ICA) is a flavonoid compound. ICA has multifarious pharmacological effects such as anti-depression, improvement of ischemic brain injury, anti-dementia, and anti-aging. Research on Alzheimer's disease (AD) has found that ICA possesses certain effects, with diverse mechanisms. ICA can reduce amyloid-β deposition to improve the symptoms of AD animal models, and its mechanism of action may be associated with the regulation of PI3K/AKT. In the nervous system, ICA can antagonize the damaging effect of neurotoxins on neurons in the rat cortex and hippocampus, and its mechanisms may be achieved by inhibiting the activation of microglia cells, reducing the production of inflammatory cytokines, alleviating the damage of inflammatory transmitters to neurons, and improving the learning and memory abilities of mice.
In the research of AD, it has been found that ferroptosis of nerve cells is a major event of nerve injury, and glial cell death also plays an important regulatory role in AD. Apart from conventional oxidative stress regulation, P53 is one of the important proteins that induce ferroptosis. P53 and MDM2 combine into a complex to regulate SLC7A11C and mediate lipid peroxidation. In this study, we attempted to further explain the role, exact mechanism and target of ICA in treating AD from the ferroptosis perspective. We found that ICA could improve the neurobehavioral, memory, and motor abilities of AD mice. It could lower the ferroptosis level and enhance the resistance to oxidative stress. After inhibition of MDM2, ICA could no longer improve the cognitive ability of AD mice, nor could it further inhibit ferroptosis. Network pharmacological analysis revealed that MDM2 might be the target of ICA action.
Particulate Air Pollution and Its Effects on the Mechanisms of Degenerative Aging
There is a great deal of data on air quality for researchers to peruse and link to the even larger set of data on human health and mortality. This has resulted in studies demonstrating strong correlations between higher levels of particulate air pollution and raised mortality, both in the context of exposure differences between large regions, and in the variations across a single metropolitan area. A large part of the problem is smoke, with industry, wildfires, and cooking fires all contributing to this issue to different degrees in different regions. Mechanistically, these particles lead to increased chronic inflammation through their interactions with lung tissue, and raised chronic inflammation contributes to the onset and progression of all of the common fatal age-related conditions.
Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied.
Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD+ boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions.
The Brain Microbiome Theory of Alzheimer's Disease
The amyloid cascade hypothesis of Alzheimer's disease suggests that the disease arises from misfolding and aggregation of amyloid-β, which grows to disrupts brain metabolism to produce inflammation and tau aggregation in later stages of the condition. While the amyloid cascade hypothesis remains the dominant view of the causes of Alzheimer's disease, there are other views. For example, that persistent infection leads directly to a runaway feedback loop of chronic inflammation and tau aggregation. In this view, amyloid-β aggregation is a side-effect, given that amyloid-β appears to be an anti-microbial peptide, a part of the innate immune response that is expected to be present in greater amounts during a persistent infection. Here, researchers discuss the potential role of microbial colonization of the brain in Alzheimer's disease, while noting that the evidence remains much debated.
Controversies surrounding the validity of the toxic proteinopathy theory of Alzheimer's disease have led the scientific community to seek alternative theories in the pathogenesis of neurodegenerative disorders (ND). Recent studies have provided evidence of a microbiome in the central nervous system. Some have hypothesized that brain-inhabiting organisms induce chronic neuroinflammation, leading to the development of a spectrum of NDs. Bacteria such as Chlamydia pneumoniae, Helicobacter pylori, and Cutibacterium acnes have been found to inhabit the brains of ND patients. Furthermore, several fungi, including Candida and Malassezia species, have been identified in the central nervous system of these patients.
However, there remains several limitations to the brain microbiome hypothesis. Varying results across the literature, concerns regarding sample contamination, and the presence of exogenous DNA have led to doubts about the hypothesis. These results provide valuable insight into the pathogenesis of NDs. Herein, we provide a review of the evidence for and against the brain microbiome theory and describe the difficulties facing the hypothesis. Additionally, we define possible mechanisms of bacterial invasion of the brain and organism-related neurodegeneration in NDs and the potential therapeutic premises of this theory.