Fight Aging!

Axons that connect neurons in the nervous system are sheathed in structures largely made of myelin. This myelin sheath is necessary for the correct function of nerves and the brain, as demonstrated by the unpleasant consequences of demyelinating conditions such as multiple sclerosis. In normal aging there is a lesser degree of loss of myelin over time, and a weight of evidence points towards this loss providing a meaningful contribution to age-related cognitive decline. Therefore it is worth keeping an eye on this area of research, and the development of therapies for demyelinating conditions, as some approaches might also be applicable to age-related myelin loss.

Myelin is maintained by the population of cells called oligodendrocytes. Like all cell populations, there is a drift away from youthful function with age. Numerous causes exist, including the usual suspects of increased inflammatory signaling and diminished stem cell and progenitor cell activity, but as is usually the case it is challenging to assign a relative importance to the many identified processes of oligodendrocyte aging. Cellular biochemistry remains an interconnected web of incompletely understood processes, only slowly mapped.

Oligodendrocytes in the aging brain

Although the exact mechanisms of cognitive decline are not yet known, it is understood that progressive breakdown of the intricate communication between neurons and glial cells, reduced efficacy of action potential conduction and processes such as neuroinflammation lead to a non-autonomous and gradual loss of cognitive function. White matter tracts functionally connect various areas of the central nervous system (CNS), and are predominantly populated by myelinated axons.

This has led to a growing field of interest and understanding of brain aging as a network deterioration, such that the loss of myelination in white matter tracts which connect cortical regions underlies the loss of cognitive functions which rely on this network connectivity and efficient neuronal transmission. Non-human primate work has found direct links between reduced myelination index, of specific corticocortical and corticobasal tracts and cognitive performance in normal aging.

Myelin is a lipid-rich membrane structure, which wraps concentrically around axons. In the CNS, myelin is provided by terminally differentiated cells of the oligodendrocyte lineage, which hereafter will be referred to as mature oligodendrocytes. Developmental myelination of the CNS takes place largely within the first 2 years of life, but white matter volume increases up until around mid-life as new axonal projections become myelinated. Adult myelination is highly plastic, modifiable by experience, and seems to have important roles in learning and memory and normal cognitive function. Oligodendrocytes are derived from specific neural progenitor cells; oligodendrocyte progenitor cells (OPCs). OPCs populate the CNS, and proliferate throughout life to self-renew, and differentiate to provide a continuous source of new mature oligodendrocytes.

It is widely accepted that there is an overall loss in white matter volume with age in non-pathologically aging human brains. Considering the widespread and specialised roles of myelin, it follows that myelin degradation leads to cognitive decline during 'normal' aging, that is in the absence of clinical age-related pathology such as dementia. This is not least as a result of leaving axons exposed and vulnerable to damage, as is well documented in demyelinating conditions such as multiple sclerosis. Longitudinal data shows that age-related myelin degeneration largely contributes to loss of cognitive function through disconnection of cortical regions, due to slowed processing speeds, which in fact appears to be independent of axonal degeneration. White matter loss and degeneration may result in age-related cognitive decline via several independent mechanisms.

The chronology of neuronal loss and myelin damage is not yet understood. Therefore, it could be hypothesised that a good understanding of the health of oligodendrocytes in the aging brain and how white matter might be protected in aging is ever more important as a potential prophylactic approach to age-associated disease.

As this paper notes, Pol III is downstream of mTORC1, and like mTORC1, inhibition extends life span in a variety of laboratory species. The network of genes around mTOR relates to the regulation of cellular responses to stress, such as increased autophagy. It is complex and touches upon many aspects of cellular metabolism. Upregulation of these stress response mechanisms, such as via the practice of calorie restriction, improves health and extends life in short lived species. It has similar effects on health in long-lived species such as our own, but the effects on lifespan are much smaller. Calorie restriction extends life by 40% in mice, but does not add more than a few years to human life span.

The transcription of the eukaryotic nuclear genome is performed by three, evolutionarily conserved, multi-subunit RNA polymerases (Pols) that each transcribe a distinct set of genes. A large proportion of the nuclear genome is transcribed by Pol II to generate both coding and non-coding RNAs. In contrast, Pol I only transcribes a single gene, albeit present in multiple copies within the genome, to produce the precursor to most rRNAs. While Pol I and III transcribe fewer genes, they generate some of the most abundant cellular RNAs accounting for much of the cellular transcriptional activity.

Pol III function has also extended beyond the canonical role in transcription of the nuclear genome to now include responses to DNA viruses and homologous recombination-mediated repair of DNA double-strand breaks. Pol III mediated transcription is involved in a wide range of biological processes including cell and organismal growth, cell cycle, stemness and differentiation, development, regeneration, and cellular responses to stress. As a result, Pol III subunits have been implicated in a wide variety of disease states.

More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. The evolutionary conservation of Pol III affirms its potential as an exciting, novel therapeutic target for ageing and age-related health.

Link: https://doi.org/10.3389/fgene.2021.705122

The exposome is the set of environmental exposures that can affect health, aging, and longevity. As presently considered by epidemiologists, the exposome can include lifestyle choices, as well as the burden of infections, particulate air pollution, and so forth. Confusingly, the concept has also been expanded to include internal factors such as hormone levels, oxidative stress, inflammation, and presence of age-related disease. Here, researchers demonstrate the sort of investigation of the exposome that can be accomplished with a large epidemiological database such as the UK Biobank. Most of the correlations reported are much as one would expect, but a couple of them are surprising.

Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach.

A total of 4,587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset.

Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77), ischemic heart disease (0.66), angina (0.73), Alzheimer's disease (0.80), hypertension (0.70), type 2 diabetes (0.88), high cholesterol (0.81), and venous thromboembolism (0.92). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36) showed the opposite.

Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at age 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite.

In conclusion, the present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.

Link: https://doi.org/10.1186/s12916-021-02030-4

The aging of the gut microbiome is a topic of growing interest in the research community. It is possible that changes to the gut microbiome have an effect on the progression of aging that is in the same ballpark as that of exercise. With advancing age, harmful inflammatory microbial species grow in number, while those that produce beneficial metabolites decline in number. This has consequences, both the rise of chronic inflammation and loss of tissue function. As today's open access review paper notes, this reaches even to the brain, separated as it is from much of the biochemistry of the rest of the body by the blood-brain barrier.

The immune cells of the brain, such as microglia, follow the rest of the immune system in becoming more inflammatory and dysfunctional with age. Evidence strongly suggests that this neuroinflammation is an important component driving the progression of age-related neurodegenerative conditions. How much of this is connected to the altered gut microbiome present in old individuals? Arguably a meaningful enough fraction to work towards treatments that can restore a youthful microbial population to older individuals. There are approaches close to realization, that would not take an excessive effort to bring to the clinic, such as repurposing fecal microbiota transplantation for use with young donors and old recipients. When conducted in short-lived animal models, that treatment improves heath and extends life.

Getting on in Old Age: How the Gut Microbiota Interferes With Brain Innate Immunity

The interaction between the gut microbiota and the innate and adaptive immune systems through direct engagements at mucosal surfaces or microbiota derived metabolites is unambiguous. The peripheral immune system is quite sensitive to slight alterations in the circulating metabolites and plasma cytokine composition, which can result due to microbiota dysbiosis. Intriguingly, parabiosis or plasma transfer experiments that expose a young animal to old blood decreases hippocampal neurogenesis, promotes microgliosis and, ultimately, impairs learning and memory function. On the other hand, exposing aged animals to young blood improves the cerebral vasculature, enhances neurogenesis in the subventricular zone and ameliorates the decline in olfaction.

The brain has long been thought to be immune-privileged. However, the test of time has proved this terminology not absolute. Under homeostatic conditions, the degree of immune-privilege varies depending on age and neurological health. Additionally to the aforementioned age-associated alteration of the microbiota in aging, the neurovascular unit of the blood-brain barrier undergoes a transition which could potentially allow atypical primary or secondary microbiota-derived molecules uptake into the central nervous system (CNS). Indeed, beyond peripheral immunity, microbiota-derived signaling molecules have been implicated in CNS immunity, neuropsychiatric, and neurodegenerative disorders

Compared to other understudied CNS innate immune cells, the microbiota-microglia axis has been well investigated during development and adulthood. There is an evident gap in understanding the direct and indirect links between the microbiota and CNS innate immune cells other than microglia. This gap is even wider when it comes to investigating these interactions in the context of aging. It is difficult to comprehend the biological and molecular basis of senescence, as well as the interplay between microglial senescence and the gut microbiota regulating various functions in the healthy and diseased brain. This, however, represents a therapeutic opportunity that could lead to the discovery of new pharmacological targets for maintaining or restoring physiological tasks in long-lived individuals.

The practice of calorie restriction (also known as dietary restriction) improves health and slows aging. This occurs to a greater degree in short-lived species than in our own comparatively long-lived species, but nonetheless, the benefits are evident. Researchers here discuss the evidence for calorie restriction to be protective of kidney function, but for that protection to decline with age. This is an interesting perspective on calorie restriction, one that I haven't see much mentioned in the past. Very little of our biochemistry and function escapes aging, and we might expect near any measurable aspect of physiology and metabolism to become worse in older people. So why not also a reduction in the ability of our metabolism to respond favorably to a lower calorie intake?

Dietary restriction (DR) is believed to be one of the most promising approaches to extend life span of different animal species and to delay deleterious age-related physiological alterations and diseases. Among others, DR was shown to ameliorate acute kidney injury (AKI) and chronic kidney disease (CKD). However, to date, a comprehensive analysis of the mechanisms of the protective effect of DR specifically in kidney pathologies has not been carried out.

The protective properties of DR are mediated by a range of signaling pathways associated with adaptation to reduced nutrient intake. The adaptation is accompanied by a number of metabolic changes, such as autophagy activation, metabolic shifts toward lipid utilization and ketone bodies production, improvement of mitochondria functioning, and decreased oxidative stress. However, some studies indicated that with age, the gain of DR-mediated positive remodeling gradually decreases. This may be an obstacle if we seek to translate the DR approach into a clinic for the treatment of kidney diseases as most patients with AKI and CKD are elderly.

It is well known that aging is accompanied by impairments in a huge variety of organs and systems, such as hormonal regulation, stress sensing, autophagy and proteasomal activity, gene expression, and epigenome profile, increased damage to macromolecules and organelles including mitochondria. All these age-associated changes might be the reasons for the reduced protective potential of the DR during aging. Here we summarize the available mechanisms of DR-mediated nephroprotection and describe ways to improve the effectiveness of this approach for an aged kidney.

Link: https://doi.org/10.3389/fphys.2021.699490

Changes in the regulation of inflammatory signaling in aging is just as complicated as any other aspect of the metabolic shifts that occur with age. A raised level of chronic inflammation is very definitely a bad thing, and contributes to the onset and progression of all of the common age-related conditions. It isn't clear that regulators of inflammation are the right place to intervene, versus deeper causes that provoke the regulators into action, however. The aging body generates a far greater level of prompts that rouse the immune system into inflammation, in comparison to a young body, a range of consequences of cellular damage and dysfunction that could themselves be targets for repair-based therapies. Removal of lingering senescent cells, for example, which secrete pro-inflammatory cytokines and are shown to produce chronic inflammation.

Chronic loss of cardiomyocyte integrity underlies human heart failure (HF) associated with aging that often involves progression of acute myocardial infarction (MI) and the maladaptive response of cardiomyopathy. During MI, the membrane repair function of cardiomyocytes is compromised, and protection of membrane integrity is an important strategy to treat MI and HF. In addition, chronic oxidative stress and inflammation associated with aging can render the cardiomyocytes more susceptible to stress-induced MI. Therefore, a therapeutic approach that restores tissue integrity and mitigates inflammation can potentially be an effective means to treat age-related organ dysfunction.

We previously identified MG53 as an essential component of cell membrane repair. MG53 nucleates the assembly of the membrane repair machinery in a redox-dependent manner. Mice without the MG53 gene develop cardiac pathology due to defective membrane repair and increased susceptibility to cardiac injury. Transgenic mice with sustained elevation of MG53 in the bloodstream (~100 fold higher circulating MG53 vs wild type mice) lived a healthier and longer lifespan compared with the littermate wild type mice, and displayed increased tissue healing and regeneration capacity following injury. While we have demonstrated that intravenous administration of recombinant human MG53 (rhMG53) protein could protect against acute heart injury in rodent and porcine models of ischemia-reperfusion induced MI, whether rhMG53 has beneficial effects on chronic HF remains to be determined.

Here we demonstrate that the expression of MG53 is reduced in failing human heart and aging mouse heart, concomitant with elevated NFκB activation. We evaluate the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements reveal beneficial effects of rhMG53 treatment in improving heart function of aging mice. Biochemical and histological studies demonstrate the cardioprotective effects of rhMG53 are linked to suppression of NFκB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administrations of rhMG53 in aged mice do not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.

Link: https://doi.org/10.1172/jci.insight.148375

Greater personal wealth very clearly correlates with modestly greater longevity. Why is this? That is a hard question to answer, as the network of correlations between socioeconomic status, education, wealth, intelligence, and lifestyle choices are challenging to pick apart in most available databases of epidemiological information. Are wealthier people on balance more educated, and more educated people tend to take better care of their health? Are wealthier people wealthy because they tend to be more proactive in all aspects of life, and thus also make better use of the opportunities provided by medical technology? Are wealthier people better equipped culturally by their upbringing to take better care of their health? Does greater intelligence, and thus greater capacity to become wealthy, derive from gene variants that also produce physical robustness and a longer life span? And so forth.

The study here is interesting for looking into the correlation between personal wealth and the later life survival of siblings and twins, as well as a more general population. Comparing siblings can eliminate many of the questions regarding, for example, the effects of upbringing in a wealthier environment on lifestyle choice, or the possibility of pleiotropic effects of genetic variants on both intelligence and physical robustness. The researchers find that wealth effects on longevity, whatever the underlying cause, appear to be much the same between siblings and non-siblings. This by no means points to a definitive explanation for the correlations observed, but it does make some of the existing hypotheses less likely to be true.

Association of Wealth With Longevity in US Adults at Midlife

Socioeconomic disparities in life expectancy are substantial in size. Financial wealth or net worth, which is the value of an individual's assets (such as savings, real estate, and vehicles) minus liabilities, is directly associated with longevity. However, a challenge in this area of research has been eliminating or minimizing the potential for confounding by the early environment and heritable traits, either of which could simultaneously affect socioeconomic conditions in adulthood and health in the course of life.

Full siblings who were raised in the same family share much of their early rearing environment and are genetically related to one another. Thus, in sibling-comparison studies, factors that are shared between siblings are controlled. Twin comparisons provide an even greater control of family-level early-life confounding and, in the case of monozygotic (MZ) twins, control for all heritable genetic factors. Previous research found that discordance in occupational prestige was associated with cardiovascular risk and overall mortality; twins with lower-prestige jobs had worse health on both outcomes compared with their co-twins with higher-prestige jobs. This pattern suggests that socioeconomic disparities in health are affected by experiential factors in adulthood over and above any potential confounders that involve the siblings' shared early environment and genetic characteristics. In other discordant sibling and twin analyses, educational attainment and composite measures of adult socioeconomic position also have been associated with better adult health outcomes and longevity. However, results from these and other studies that used different methods do suggest these associations may be partially explained by shared family-level environmental factors or genetic predispositions.

Comparatively little attention has been given to wealth disparities, a potentially important oversight. In this cohort study, we used a discordant sibling design to conservatively estimate the association between wealth and longevity. Specifically, we aimed to identify the association between net worth at midlife (the middle years of life) and subsequent all-cause mortality in individuals as well as within siblings and twin pairs. We posed two research questions. First, was wealth accumulation at midlife associated with longevity over a nearly 24-year follow-up? Consistent with previous work, we expected that higher wealth accumulation would be associated with increased longevity. Second, was the wealth-longevity association present over and above controls for family and heritable factors that could confound this association?

In this cohort study of 5,414 participants in the Midlife in the United States study, those who had accumulated a higher net worth by midlife had significantly lower mortality risk over the subsequent 24 years. In sibling and twin comparison models that controlled for shared early life experiences and genetic influence, the association between net worth and longevity was similar in magnitude. Thus net worth at midlife was associated with longevity among adults in the study, and this association is unlikely to be merely an artifact of early experiences or heritable traits shared by families.

Osteoporosis is more prevalent in older women than in older men, for reasons related to estrogen deficiency, but the detailed mechanisms remain less clear than clinicians would like them to be. Many aspects of aging are correlated with one another. Aging is a burden of damage and consequences of that damage, progressing at modestly different paces in different individuals, largely due to variations in lifestyle choices and environmental exposure to persistent pathogens. Genetics plays some role, but probably only a small role in near all people. Thus more damage gives rise to a greater risk of many different age-related conditions in the same individual. Still, in some cases, one condition can contribute directly to another. For example, to the extent that osteoporosis restricts activity (and thus vascular health, cerebral blood flow, and so forth), it will likely harm cognitive health over time.

Dementia and osteoporosis are highly prevalent in the elderly population and often coexist. Individuals with dementia are at high risk of osteoporosis and hip fracture. It has been estimated that approximately 40% of patients with hip fracture have a prior diagnosis of dementia. The risk of hip fracture in Alzheimer's disease was recently reported in a meta-analysis of nine cohorts from the United States, Canada, and the UK to be over twofold compared to those without dementia. Furthermore, this study also demonstrated that hip bone mineral density (BMD) was lower in those affected compared to controls.

Notably, a recent study has demonstrated increased risk of dementia following both hip and non-hip fractures. Although the risk of dementia was highest following hip fracture (60%), vertebral (47%), lower (35%), and upper limb (29%) fractures were also associated with increased risk. These findings are particularly important as non-hip fractures are very common, affecting two in five women and one in three men after the age of 60 years.

The nature of the association between osteoporosis and dementia is not entirely clear. Most authors to date believe that the association between these two common conditions is likely driven by common risk factors such as old age, sedentary lifestyle, physical decline, vitamin D insufficiency, sarcopenia, and propensity to falls. However, there is some evidence that suggests that hip fracture per se may lead to complications which directly precipitate dementia development. Furthermore, at least two studies have shown a significant association between low BMD or bone loss and subsequent cognitive decline in postmenopausal women. However, studies investigating the longitudinal long-term association between cognitive decline and both bone loss and fracture risk are lacking.

This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Over 95% of participants had normal cognition at baseline. After multivariable adjustment, cognitive decline was associated with bone loss in women but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly. There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women

Link: https://doi.org/10.1002/jbmr.4402

Calorie restriction is perhaps the most studied of all interventions known to slow aging, and yet undergoing calorie restriction changes so much of metabolism that it remains a challenge to understand which of the countless mechanisms involved are important. It is clearly the case that the cellular maintenance processes of autophagy are critical, as researchers have shown that when autophagy is sabotaged via genetic engineering, calorie restriction no longer produces its well-known benefits to health and longevity. Beyond that, different research groups peer intently at very localized portions of cell and tissue biochemistry, and seem likely to continue doing that well into the era in which calorie restriction, and the entire concept of slowing aging via metabolic adjustment, is surpassed by rejuvenation therapies based on periodic repair of the molecular damage that causes aging.

Endothelin-1 (ET-1) is a potent vasoconstrictor synthesized by vascular endothelial cells that is normally present at low plasma concentrations. ET-1 plays a significant role in kidney physiology and pathology, highlighted by the fact that ET-1 transgenic mice undergo spontaneous kidney fibrosis even in the absence of hypertension. Ageing is associated with an increase in ET-1 levels in the renal vasculature. Elevated ET-1 can increase reactive oxygen species (ROS), which in turn can increase the uptake of oxidized low-density lipoprotein (ox-LDL) by increasing the expression of its cognate receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), cumulatively contributing to endothelial dysfunction. Indeed, pre-clinical studies with endothelin receptor antagonists have shown promising results in alleviating ageing-induced impairment of renal function.

Caloric restriction (CR) can reduce the ageing process and related organ dysfunction in most species. CR without malnutrition is a dietary regimen that delays ageing and extends the lifespan. More importantly, studies in mice and rat models of ageing have shown that CR exerts significant cerebrovascular protective effects, improves cortical microvascular density and endothelial function, and counteracts ageing-induced alterations in renal function, including glomerulosclerosis and alterations in glomerular filtration. CR also improved vascular health by eliciting changes in the levels of circulating neuroendocrine factors.

Given this background, the objective of the current study was to investigate whether CR counteracts ageing-induced alterations in renal function and inflammatory cytokines by impacting ET-1 levels. We found that ET-1 messenger RNA (mRNA) and protein expression were increased ex vivo in the renal artery segments of 12-month-old rats compared to 2-month-old rats, which was reversed when rats were subjected to CR. Functional assays showed that CR alleviated renal dysfunction and decreased the expression of pro-inflammatory cytokines by decreasing ET-1 expression.

Link: https://doi.org/10.21037/atm-21-2218

Parkinson's disease is the best known of the synucleinopathies, age-related neurodegenerative conditions characterized by the damaging aggregation of misfolded α-synuclein. This is one of only a few proteins in the body that can misfold in ways that encourage other molecules of the same protein to also misfold, creating a contagion that can slowly spread from cell to cell, and aggregate into toxic structures that disrupt cell function and kill cells.

Today's research materials examine some of the details of the spread of misfolded α-synuclein. This is an important topic for the same reasons that metastasis of cancer is an important topic. Finding ways to prevent the spread to neighboring tissue would remove the worse aspects of both cancer and synucleinopathies, restricting them to localized harm. This requires a comprehensive exploration of the biochemistry involved, as a priori it is hard to say which of the presently unknown or poorly understood details will turn out to be useful.

It has become clear in recent years that mammalian cells can and do exchange component parts with one another. There is considerable evidence for the transfer of mitochondria, for example. Cells with functional mitochondria have been observed attempting to rescue cells with damaged mitochondria, extending structures called tunneling nanotubes that link two cells together, and passing mitochondria through that connection. Here, researchers observe cells doing this in order to transfer lysosomes, which act as recycling units in cells, responsible for breaking down damaged and unwanted molecules. The misfolding of α-synuclein hijacks this process in a way that favors transmission of misfolded proteins between cells, carried within damaged lysosomes.

Parkinson's disease: how lysosomes become a hub for the propagation of the pathology

The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several neurodegenerative diseases (NDs). Mounting evidence in cellular and in animal models highlights the capability of different misfolded proteins to be transmitted and to induce the aggregation of their endogenous counterparts, this process is called "seeding". In Parkinson's disease, the second most common ND, misfolded α-synuclein (α-syn) proteins accumulate in fibrillar aggregates within neurons. Those accumulations are named Lewy bodies.

In 2016, a team of researchers demonstrated that α- syn fibrils spread from donor to acceptor cells through tunneling nanotubes (TNTs). They also found out that these fibrils are transferred through TNTs inside lysosomes. Following this original discovery, researchers now shed some light on how lysosomes participate in the spreading of α-syn aggregates through TNTs. "By using super-resolution and electron microscopy, we found that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. We demonstrated for the first time that α-syn fibrils induce the peripheral redistribution of the lysosomes thus increasing the efficiency of α-syn fibrils' transfer to neighbouring cells."

They also showed that α-syn fibrils can permeabilize the lysosomal membrane, impairing the degradative function of lysosomes and allowing the seeding of soluble α-syn, which occurs mainly in those lysosomes. Thus, by impairing lysosomal function α-syn fibrils block their own degradation in lysosomes, that instead become a hub for the propagation of the pathology.

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a "prion-like" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells.

We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them.

These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

The results reported here are intriguing, suggesting that some aspects of the extracellular matrix structure in the brain are of great importance to neural plasticity loss of memory function with age, at least in mice. This is quite novel. Most work on neurodegeneration touches only lightly, if at all, on the structure and composition of the extracellular matrix. Researchers here used a gene therapy to adjust the proportion of different chondroitin sulphates in matrix structures in old mice, and the resulting restoration of memory function is quite impressive.

Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity - the ability of the brain to learn and adapt - and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain. Their main function is to control the level of plasticity in the brain. They appear at around five years old in humans, and turn off the period of enhanced plasticity during which the connections in the brain are optimised. Then, plasticity is partially turned off, making the brain more efficient but less plastic.

PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.

Researchers investigated whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate age-related memory deficits. To do this, the team looked at 20-month old mice - considered very old - and using a suite of tests showed that the mice exhibited deficits in their memory compared to six-month old mice. The team treated the ageing mice using a 'viral vector', a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs and found that this completely restored memory in the older mice, to a level similar to that seen in the younger mice.

Link: https://www.cam.ac.uk/research/news/scientists-reverse-age-related-memory-loss-in-mice

Frailty is a condition with a strong inflammatory component. It isn't just physical weakness, but also the vulnerability of an incapable and constantly overactive immune system, generating inflammatory signaling that disrupts tissue and organ function throughout the body. In recent years, there has been a considerable growth of interest in the gut microbiome and its contribution to aging. It is clear that microbial populations shift with age in ways that promote inflammatory engagement with the immune system. Replacing an old gut microbiome with a young gut microbiome, such as via fecal microbiota transplantation, produces a reduction in inflammation, improvement in function, and extension of life span in short-lived animal models. This is an approach to rejuvenation that could be fairly rapidly developed for human use, and certainly should receive more attention and funding than is presently the case.

Frailty is a clinical syndrome characterized by "diminished strength, endurance, and reduced physiological function". Frailty predisposes patients to negative health-related outcomes such as falls, hospitalization, disability, dependency, and mortality. The prevalence of frailty ranges from 4% to 59% in community-dwelling older adults and increases with age. Given the rapidly aging population, the United Nations estimates that worldwide, the number of people aged 60 years and above will double to nearly 2.1 billion by 2050. Therefore, frailty is a pressing concern in aging societies.

Microorganisms, as an environmental factor, are among the most interesting contributors to aging, and they provide a new perspective in understanding the aging process. As a person ages, progressive changes in intestinal tract physiology, the intestinal mucosal immune system, lifestyle changes (particularly in diet and exercise), medication, malnutrition, inflammation, and immune senescence may change the diversity, composition, and functional features of the gut microbiota. Data from animal models demonstrate that age-related microbial dysbiosis contributes to intestinal permeability, systemic inflammation, and premature mortality. Though the cause-and-effect relationship is unclear, age-related microbial dysbiosis is linked to unhealthy aging and geriatric syndromes, which include frailty. Identifying specific changes in frailty-related gut microbiota is essential in developing microbiome-based diagnostic and therapeutic strategies.

In this review, we first describe the relevant changes in gut microbiota related to aging and frailty. Subsequently, we summarize recent findings on the possible role of chronic low-grade inflammation in frailty and how microbial dysbiosis is involved in its pathogenesis, including frailty-related inflammation.

Link: https://doi.org/10.3389/fcimb.2021.675414

An interesting body of scientific work exists to investigate the question of whether or not various forms of electromagnetic stimulation can improve tissue function, particularly in older people. To improve neurogenesis in an aging brain, or enhance nerve regrowth following injury, for example. Taken broadly, the manipulation of cells to specific ends via electromagnetism is far less studied than is the case for the use of small molecules, however, and this is very evident in the character of the data.

Picking any one approach to electromagnetic therapy at random, one tends to find unpromising results, when taken as a whole, meaning a few flashes of claimed success amidst a great deal of failure. There is reason to believe that the fine details of equipment, experimental setup, duration of treatment, and frequency of electromagnetic radiation are all important, and that perhaps consistent success is a matter of finding the right combination for a given application. That may or may not be the case.

Transcranial direct current stimulation has the merit of having perhaps fewer important variables to adjust in terms of how the treatment is delivered, which might explain why the data looks somewhat better for this approach than for others I've seen. That is a low bar, but still. Today's open access paper provides a review of the literature on this topic, which at the end of the day suggests that some approaches can beneficially affect at least some functions in the aging brain. Considerable uncertainty remains.

Can Transcranial Direct Current Stimulation Enhance Functionality in Older Adults? A Systematic Review

Transcranial direct current stimulation (tDCS) is a non-invasive tool for neuromodulation that has proven to be well-tolerated and safe. This technique employs low-intensity continuous or galvanic current applied transcutaneously via electrodes placed on the scalp. The change generated in the electric potential of the membrane of the underlying neurons affects neuronal excitability, which varies depending on the orientation of the electric field determined by the position and polarity of the electrodes. This effect on excitability is believed to be related to transient changes in the synaptic efficiency of different neurotransmitters.

Complex structural and functional changes in the brain are some of the processes related to normal aging that entail deterioration of cognitive, perception, and motor capacities, which affects daily life activities, independence, and quality of life. The main finding observed is the increase in dual-task costs, and the most affected ability due to aging is the simultaneous execution of one motor and one cognitive task. Additionally, older adults present a reduction in the structural and functional plasticity of the brain and in flexibility for tasks requiring previous learning. Trials using neuroimaging indicate that the left dorsolateral prefrontal cortex (DLPFC), which intervenes in the executing function, is one of the key brain regions involved in performing combined cognitive and motor tasks under dual-task conditions. For this reason, tDCS interventions designed for facilitating the functional activation of the DLPFC and its neuronal networks could improve the cognitive function and motor performance in the elderly.

This systematic review aimed at compiling and summarizing the currently available scientific evidence about the effect of tDCS on functionality in older adults over 60 years of age. A search of databases was conducted to find randomized clinical trials that applied tDCS versus sham stimulation in the above-mentioned population. No limits were established in terms of date of publication. A total of 237 trials were found, of which 24 met the inclusion criteria. Finally, nine studies were analyzed, including 260 healthy subjects with average age between 61.0 and 85.8 years. Seven of the nine included studies reported superior improvements in functionality variables following the application of tDCS compared to sham stimulation. Anodal tDCS applied over the motor cortex may be an effective technique for improving balance and posture control in healthy older adults. However, further high-quality randomized controlled trials are required to determine the most effective protocols and to clarify potential benefits for older adults.

Intermittent fasting strategies, such as alternate day fasting, are known to slow aging in a variety of species. The mechanisms are likely similar to those involved in the calorie restriction response, meaning upregulation of stress responses and cellular maintenance, though intermittent fasting is capable of producing some degree of benefits even when overall calorie intake is not reduced. Time spent in a state of hunger, and the consequent reactions of cells and tissues, is clearly an important factor. The human data for both calorie restriction and intermittent fasting shows health benefits, and from what is known of the mechanisms involved it is reasonable to propose that calorie restriction or intermittent fasting could modestly slow at least some forms of neurodegenerative condition.

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting ~2% of the population over age 70. Disease prevalence increases with age and, given the aging population, may triple in the next few years. The neurodegenerative mechanism leading to PD is still not completely elucidated. Alpha-synuclein may drive the neurodegenerative process of PD. When aggregated in neurons as intracellular Lewy bodies, it constitutes the pathologic hallmark of PD. On the other hand, mitochondrial dysfunction, oxidative stress, and selective neuronal loss each contribute to PD pathology.

Unfortunately, there remains no disease-modifying treatment in PD despite multiple trials of promising preclinical targets. Supplements and dietary interventions have been periodically considered as possible therapeutic approaches to impact disease progression and severity in related neurodegenerative disorders. One such intervention is intermittent fasting (IF). This viewpoint seeks to describe the putative pathophysiologic relationships among mitochondria, alpha-synuclein, and PD risk genes, and to provide a background for the rationale or the use of IF and similar mitochondrial-targeting therapies in PD. Finally, we propose an outline for determining the efficacy of an IF intervention in PD.

Link: https://doi.org/10.3389/fneur.2021.682184

When faced with long-lasting challenges, such as cancer or persistent infections that the immune system struggles to clear, T cells of the adaptive immune system can become exhausted. The exhausted cells lose function, diminishing both the immediate immune response and the ability to form immune memory that will enable a robust future response to the same threat. Researchers see this in the engineered T cells used in chimeric antigen receptor (CAR) T cell therapies, and there is thus a strong incentive to find ways to address the issue by identifying important causes or regulators of T cell exhaustion, and interfering to prevent it.

Fighting a tumor is a marathon, not a sprint. For cancer-fighting T cells, the race is sometimes just too long, and the T cells quit fighting. Researchers even have a name for this phenomenon: T cell exhaustion. Researchers now report that T cells can be engineered to clear tumors without succumbing to T cell exhaustion. This research builds on work that has shown the key role of proteins called transcription factors in the cellular pathway that triggers T cell exhaustion. This work is important because T cell exhaustion continues to plague even the most cutting-edge cancer immunotherapies.

With CAR T therapies, for example, researchers take T cells from a cancer patient and "arm" them by altering the expression of genes that aid in the cancer fight. Researchers make more of these special T cells, which then go back into the patient. CAR T therapies are different from immunotherapies, which aim to activate the patient's existing T cell population. With both approaches, T cell exhaustion rears its ugly head. "Many people have tried to use CAR T therapies to kill solid tumors, but it's been impossible because the T cells become exhausted."

The new study addresses this problem by giving T cells the ability to fight exhaustion itself. To accomplish this, the researchers screened T cells to uncover which transcription factors could boost a T cell's "effector" program, an important step in readying T cells to kill cancer cells. This screening process led the researchers to BATF, a transcription factor that they found cooperates with another transcription factor called IRF4 to counter the T cell exhaustion program.

In mouse melanoma and colorectal carcinoma tumor models, altering CAR T cells to also overexpress BATF led to tumor clearance without prompting T cell exhaustion. The CAR T therapy worked against solid tumors. Encouragingly, some altered T cells also stuck around and became memory T cells. This is important because T cell exhaustion often prevents T cells from mounting a strong memory response to recurrent cancers.

Link: https://www.lji.org/news-events/news/post/preparing-t-cells-for-the-long-haul/