Fight Aging!

In today's open access paper, the authors argue that a downward trend in normal human body temperature recorded by physicians over the past 150 years is real, rather than being an artifact of changing approaches to measurement. Taking that as settled, though I'm sure there is plenty of room left to debate the point, one might then ask why this trend exists and what it might imply.

Over the past few centuries, both life expectancy at birth and adult life expectancy have risen steadily, the former more profoundly than the latter due to sizable reductions in childhood mortality. The majority of these gains in adult life expectancy have been the result of improved control over infectious disease, reducing the burden placed on the immune system over the long term by both chronic and passing infections. The authors of this paper pull from a number of sources to suggest that this burden of chronic infection is the source of raised body temperature, due to inflammation.

Does a lowered body temperature in and of itself cause differences in human longevity, or do the effects of chronic inflammation on the pace of immune aging far outweigh it? Human data is supportive of the idea that lower body temperature correlates with greater longevity, but not definitively so. The practice of calorie restriction lowers core body temperature in the course of slowing aging in mammals. But is body temperature actually an important mechanism in comparison to the others involved in chronic infection and calorie restriction? I would guess no, given what I've seen of the literature on these topics.

Decreasing human body temperature in the United States since the industrial revolution

In 1851, the German physician Carl Reinhold August Wunderlich obtained millions of axillary temperatures from 25,000 patients in Leipzig, thereby establishing the standard for normal human body temperature of 37°C. A compilation of 27 modern studies, however, reported mean temperature to be uniformly lower than Wunderlich's estimate. Recently, an analysis of more than 35,000 British patients with almost 250,000 temperature measurements, found mean oral temperature to be 36.6°C.

In this study, we analyzed 677,423 human body temperature measurements from three different cohort populations spanning 157 years of measurement and 197 birth years. We found that men born in the early 19th century had temperatures 0.59°C higher than men today, with a monotonic decrease of -0.03°C per birth decade. Temperature has also decreased in women by -0.32°C since the 1890s with a similar rate of decline (-0.029°C per birth decade). Although one might posit that the differences among cohorts reflect systematic measurement bias due to the varied thermometers and methods used to obtain temperatures, we believe this explanation to be unlikely.

The question of whether mean body temperature is changing over time is not merely a matter of idle curiosity. Human body temperature is a crude surrogate for basal metabolic rate which, in turn, has been linked to both longevity (higher metabolic rate, shorter life span) and body size (lower metabolism, greater body mass). We speculated that the differences observed in temperature between the 19th century and today are real and that the change over time provides important physiologic clues to alterations in human health and longevity since the Industrial Revolution.

Resting metabolic rate is the largest component of a typical modern human's energy expenditure, comprising around 65% of daily energy expenditure for a sedentary individual. Heat is a byproduct of metabolic processes, the reason nearly all warm-blooded animals have temperatures within a narrow range despite drastic differences in environmental conditions. Over several decades, studies examining whether metabolism is related to body surface area or body weight, ultimately, converged on weight-dependent models. Since US residents have increased in mass since the mid-19th century, we should have correspondingly expected increased body temperature. Thus, we interpret our finding of a decrease in body temperature as indicative of a decrease in metabolic rate independent of changes in anthropometrics.

Although there are many factors that influence resting metabolic rate, change in the population-level of inflammation seems the most plausible explanation for the observed decrease in temperature over time. Economic development, improved standards of living and sanitation, decreased chronic infections from war injuries, improved dental hygiene, the waning of tuberculosis and malaria infections, and the dawn of the antibiotic age together are likely to have decreased chronic inflammation since the 19th century. For example, in the mid-19th century, 2-3% of the population would have been living with active tuberculosis. Although we would have liked to have compared our modern results to those from a location with a continued high risk of chronic infection, we could identify no such database that included temperature measurements. However, a small study of healthy volunteers from Pakistan - a country with a continued high incidence of tuberculosis and other chronic infections - confirms temperatures more closely approximating the values reported by Wunderlich.

In summary, our investigation indicates that humans in high-income countries have changed physiologically over the last 200 birth years with a mean body temperature 1.6% lower than in the pre-industrial era. The role that this physiologic 'evolution' plays in human anthropometrics and longevity is unknown.

This is an interesting study; you'll have to actually look at the open access paper to see the meat of it, which is the various graphs showing the changes in relative population size of different microbe families in the gut that take place with age. A great deal of work on the gut microbiome and its role in health and aging is presently taking place in the scientific community; researchers have identified a number of beneficial metabolites that are produced by classes of microbe that decline with age. Further, the gut microbiome becomes ever more inflammatory with age. The size of these effects on health might be in the same ballpark as those of regular exercise, but the reasons why changes take place are not yet fully understood. The causative mechanisms seem fairly clear in and of themselves, meaning declining immune function, changes in diet, and so forth, but how they interact and which are primary and which are secondary is yet to be firmly resolved.

We obtained RNA sequencing data of subjects ranging from newborns to centenarians from a previous study, and summarized the data into a relative abundance matrix of genera in all the samples. Without using the age information of samples, we applied an unsupervised algorithm to recapitulate the underlying aging progression of microbial community from hosts in different age groups and identify genera associated to this progression. Literature review of these identified genera indicated that for individuals with advanced ages, some beneficial genera are lost while some genera related with inflammation and cancer increase.

A few genera were previously implicated in the literature, such as Oxalobacter, Butyrivibrio, Lactobacillus which have been experimentally demonstrated to be associated with aging, as well as Prevotellaceae which has been highlighted with lower presence in the gut microbiota of centenarians. The abundances of some other genera increased with respect to aging, but decreased in the extremely elderly subjects. Among these genera, Lactobacillus species are commonly used as probiotics. Oscillospira species have been frequently reported as enriched in lean subjects compared to the obese subjects, and are central to the human gut microbiota for degrading fibers. Oxalobacter is responsible for degrading oxalate in the gut. It has been experimentally demonstrated appearing in the gut of almost all young individuals, but these bacterium may later be lost during aging.

Prevotellaceae is commonly found in the gastric system of people who maintain a diet low in animal fats and high in carbohydrates and is lost in centenarians. Researchers also found that there was an increased abundance of Prevotellaceae in the guts of healthy people compared with people with Parkinson's disease. Parascardovia is a genus of Bifidobacteriaceae, which has been shown to provide health-promoting benefits to the host. Butyrivibrio species have been experimentally proved as butyrate producing bacteria, and butyrate is a preferred energy source for colonic epithelial cells and is thought to play an important role in maintaining colonic health in humans. Overall, the decrease of these beneficial genera in the elderly age groups, especially centenarians, maybe manifestation of or causal associations to decline of health in those age groups.

Link: https://doi.org/10.1186/s12866-019-1616-2

That cancer mortality is declining at a time in which the aged segment of the population is growing, and ever more people are overweight and obese, is a testament to (a) improved prevention (largely fewer people smoking, which has a sizable impact on lung cancer incidence and severity) and (b) the ever increasing efficacy of modern cancer treatments, particularly immunotherapies. These newer cancer therapies are still in the comparatively early stages of evolution as a technology platform, and we should expect these gains to continue. The immunotherapies of the 2030s will be very impressive in comparison to those deployed today.

The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported. The steady 26-year decline in overall cancer mortality is driven by long-term drops in death rates for the four major cancers - lung, colorectal, breast, and prostate, although recent trends are mixed. The pace of mortality reductions for lung cancer - the leading cause of cancer death - accelerated in recent years.

Overall cancer death rates dropped by an average of 1.5% per year during the most recent decade of data (2008-2017), continuing a trend that began in the early 1990s and resulting in the 29% drop in cancer mortality in that time. The drop translates to approximately 2.9 million fewer cancer deaths than would have occurred had mortality rates remained at their peak. Continuing declines in cancer mortality contrast with a stable trend for all other causes of death combined, reflecting a slowing decline for heart disease, stabilizing rates for cerebrovascular disease, and an increasing trend for accidents and Alzheimer's disease.

Lung cancer death rates have dropped by 51% (since 1990) in men and by 26% (since 2002) in women, with the most rapid progress in recent years. For example, reductions in mortality accelerated from 3% per year during 2008-2013 to 5% per year during 2013-2017 in men and from 2% to almost 4% in women. However, lung cancer still accounts for almost one-quarter of all cancer deaths, more than breast, prostate, and colorectal cancers combined.

The most rapid declines in mortality occurred for melanoma of the skin, on the heels of breakthrough treatments approved in 2011 that pushed one-year survival for patients diagnosed with metastatic disease from 42% during 2008-2010 to 55% during 2013-2015. This progress is likewise reflected in the overall melanoma death rate, which dropped by 7% per year during 2013-2017 in people ages 20 to 64, compared to declines during 2006-2010 (prior to FDA approval of ipilimumab and vemurafenib) of 2%-3% per year in those ages 20 to 49 and 1% per year in those ages 50 to 64. Even more striking are the mortality declines of 5% to 6% in individuals 65 and older, among whom rates were previously increasing.

Link: https://pressroom.cancer.org/CancerStats2020

The materials here report on efforts to screen for small molecule compounds that can reduce the age-related decline of mitochondrial function observed in neurons - and indeed throughout the body. Screening the contents of compound libraries is a process that might sound simple, and conceptually it is, but it is a complex task to build a cost-effective system and supporting logistics to screen for a novel outcome. In this case the outcome is a reversal of at least some degree of reduced mitochondrial function in neurons from old tissue, as well as improvement in important aspects of neural function.

Every cell contains a herd of a few hundred mitochondria, the distant descendants of ancient symbiotic bacteria, evolved to become fully integrated component parts of the cell. They still replicate like bacteria, can fuse and split and pass around pieces of their protein machinery, and contain a small remnant genome. Mitochondria have many roles, but are primarily responsible for producing adenosine triphosphate (ATP), chemical energy store molecules that are used to power cellular processes. This is a fairly energetic activity that has the side-effect of producing reactive oxidative molecules that damage cell structures; in a normal, youthful metabolism this is entirely compensated for by repair processes, and is in fact used as a signal. For example, it enables some of the benefits of exercise by linking increased energy production to increased cell maintenance and muscle tissue growth. Age-related disruption of ATP production is particularly important in energy-hungry tissues such as the brain and muscles. Less energy means loss of function, and in the case of the brain that contributes meaningfully to the progression of neurodegenerative conditions.

The evidence of recent years suggests that the proximate cause of the problem is changes in gene expression that impair the balance between mitochondrial fission and fusion, which in turn promotes the presence of large and damaged mitochondria that are challenging for the cellular maintenance process of mitophagy to recycle. Everything goes downhill from there. Approaches such as mitochondrially targeted antioxidants and NAD+ upregulation, both shown to modestly slow aging in laboratory species and improve tissue function in human trials, may produce their benefits in large part because they change mitochondrial behavior in ways that allow mitophagy to function more efficiently, clearing out damaged and dysfunctional mitochondria.

Compounds protect brain cells' energy organelle from damage linked to Alzheimer's, ALS, Parkinson's

A new screening platform has enabled scientists to discover a set of drug-like compounds that may powerfully protect brain cells from dangerous stresses found in Alzheimer's and other neurodegenerative diseases. The screening platform allows researchers for the first time to rapidly test libraries of thousands of molecules to find those that provide broad protection to mitochondria in neurons. Mitochondria are tiny oxygen reactors that supply cells with most of their energy. They are especially important for the health and survival of neurons. Mitochondrial damage is increasingly recognized as a major factor, and in some cases a cause, for diseases of neuronal degeneration such as Alzheimer's, Parkinson's, and ALS.

The scientists, in an initial demonstration of their platform, used it to rapidly screen a library of 2,400 compounds, from which they found more than a dozen that boost the health of neuronal mitochondria and provide broad protection from stresses found in neurodegenerative disorders. The researchers are now testing the most potent of these mitochondria-protectors in animal models of Alzheimer's, amyotrophic lateral sclerosis, and other diseases, with the ultimate goal of developing one or more into new drugs. "It hasn't yet been emphasized in the search for effective therapeutics, but mitochondrial failure is a feature of many neurodegenerative disorders and something that must be corrected if neurons are to survive. So I'm a big believer that finding mitochondria-protecting molecules is the way to go against these diseases."

Neuron-based high-content assay and screen for CNS active mitotherapeutics

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from amyloid-β toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria.

The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

Researchers here investigate the relationship between the protein complex mTORC1 and the aging of intestinal stem cells, leading to loss of function in the intestine. mTORC1 signaling increases with age in intestinal tissue and leads to exhaustion of the stem cell pool, as downstream mechanisms are triggered to suppress proliferation of these cells. Naturally, mTOR or mTORC1 inhibitors are capable of reducing this effect, though one should always compare all things related to mTOR with the effects of calorie restriction before becoming too excited by new findings. Calorie restriction acts to inhibit mTOR signaling, and the size of the health benefits that it provides should guide expectations as to the bounds of the possible for therapies that inhibit mTORC1.

Nutrient malabsorption is common among the elderly, and often causes anemia and other illnesses. Nutrients are absorbed by the intestinal villi, which are composed of a layer of intestinal epithelial cells (IECs) and the lamina propria, and the absorption activity is affected by the size and density of villi. The epithelial layer is renewed every 4-5 days by intestinal stem cells (ISCs), which generate transient amplifying (TA) progenitor cells that later differentiate into absorptive or secretory cells. It has been reported that the number and regenerative activities of ISCs are decreased in 17 to 24-month-old mice, yet whether aging affects villus function and how villus aging is controlled remain less well understood.

mTOR, a sensor of nutrients and growth factors, is a central regulator of aging and a target for lifespan and healthspan extension. mTOR forms mTORC1 and mTORC2 complexes, and mTORC1 activation promotes cell proliferation by increasing global protein synthesis and other anabolic processes. mTORC1 signaling has been shown to be required for IEC proliferation during homeostasis and regeneration, including regeneration mediated by quiescent ISCs. In addition, several studies have shown that diet restriction promotes ISC expansion via mTORC1 signaling, although conflicting results have been reported regarding the exact roles played by mTORC.

The current genetic study reveals that mTORC1, which is hyperactivated in IECs, especially ISCs and TA cells of aged mice, drives villus aging by inhibiting ISC and progenitor cell proliferation through amplifying the MKK6-p38-p53 stress response pathway. This leads to ISC exhaustion and decreases in villus size and density. The natural function of the mTOR-MKK6-p38 MAPKs-p53 pathway may be to balance mTORC1-induced overgrowth and protect cells from runaway proliferation and oncogenic transformation, which is consistent with the concept that aging acts as an anti-hyperplasia mechanism.

Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. Inhibition of mTORC1 with rapamycin for only 1.5 months partially restored the structure and function of intestinal villi in old mice. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.

Link: https://doi.org/10.1038/s41467-019-13911-x

I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role is to be evidence for a lack of correlation between amyloid-β and cognitive decline. When thinking about the early stages of loss of cognitive function, in which changes are small and subtle, one might have to consider other factors such as vascular dysfunction or other neurodegenerative conditions with quite different mechanisms that could produce these effects. The interplay and relative importance of the field of mechanisms at this stage of aging is far from clear. Nonetheless, the present mood of the scientific community and its onlookers is that of a growing revolt against the amyloid cascade hypothesis of Alzheimer's disease, so research that ties into that mood receives attention.

There has been a longstanding belief among neuroscientists, backed by scientific evidence, that beta-amyloid, a protein that can clump together and form sticky plaques in the brain, is the first sign of Alzheimer's disease. The amyloid hypothesis, as it is often referred to, suggests an archetypal cascade in which β-amyloid in the brain initiates the acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. However, now a new study is challenging the current hypothesis, with data suggesting that subtle thinking and memory differences may come before, or happen alongside, the development of amyloid plaques that can be detected in the brain.

"Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer's disease process. Much of the research exploring possible treatments for Alzheimer's disease has focused on targeting amyloid. But based on our findings, perhaps that focus needs to shift to other possible targets."

The study involved 747 people with an average age of 72. After adjusting for age, education, sex, genetic risk for Alzheimer's disease, and amyloid level at the start of the study, researchers found people with subtle thinking and memory differences had a more rapid accumulation of amyloid compared to people with normal thinking and memory skills. On a test that uses a dye to measure amyloid levels, where the average level was 1.16 for participants with subtle thinking and memory difficulties, amyloid levels in this group increased by .03 above and beyond the amyloid changes in those with normal thinking and memory skills over four years. People with subtle differences also had faster thinning of the entorhinal cortex, a brain region that is impacted very early in Alzheimer's disease.

On the other hand, researchers also found that, while people with mild cognitive impairment had more amyloid in their brains at the beginning of the study, they did not have faster accumulation of amyloid when compared to those with normal thinking and memory skills. However, they did have faster thinning of the entorhinal cortex as well as brain shrinkage of the hippocampus. "From prior research, we know that another biomarker of Alzheimer's disease, a protein called tau, shows a consistent relationship with thinking and memory symptoms. Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear."

Link: https://www.genengnews.com/news/the-alzheimers-chicken-and-egg-dilemma/

The activities of mTOR are well researched, given that mTOR inhibition slows aging in a number of species. This is one of the more prominent areas of research and development to emerge from the study of beneficial stress responses such as that produced by the practice of calorie restriction. The mTOR protein participates in cellular metabolism through a pair of protein complexes, and much of the work to date has focused on the protein complex mTORC1 rather than mTORC2.

The present consensus (though not unchallenged) is that general inhibition of mTOR, such as via the use of rapamycin, is problematic because harmful effects arise from inhibition of mTORC2, offsetting the benefits due to inhibition of mTORC1. Certainly, it is the case that inhibiting mTORC2 alone shortens lifespan in laboratory animals, while inhibiting mTORC1 alone slows aging and extends life. Thus the development of drugs based on this research has focused on specific inhibition of mTORC1; several companies have a pipeline of small molecule therapies in later stage trials.

Researchers here show that increased mTORC2 activity boosts autophagy and improves cardiac function in middle-aged flies, suggesting that the current industry of mTORC1 inhibition will soon enough be joined by an industry of mTORC2 upregulation. I remain unconvinced that the effect sizes in humans resulting from upregulated autophagy will be large enough to merit the strong focus placed on this line of research and development, at a time in which most work on more promising rejuvenation therapies continues to languish in comparison, but we shall see how it all turns out soon enough.

Study of cardiac muscles in flies might help you keep your heart young

The researchers' approach starts with autophagy, a cellular "cleanup process" that removes and recycles damaged proteins and organelles. The autophagy process slows with age, which can lead to the weakening of cardiac muscles. The research team looked at a key genetic pathway conserved in virtually all organisms on Earth related to autophagy that balances organism growth with nutrient intake. This pathway, called mechanistic target of rapamycin (or mTOR), has long been linked to tissue aging. One of two complexes that underlie the mTOR pathway, referred to as mTORC2, decreases with age as autophagy declines. But the researchers found that transgenically boosting mTORC2 strengthens heart muscles of older fruit flies. "Boosting the complex almost fully restored heart function."

The discovery that enhancing mTORC2 slows the decline of the critical autophagy process could have big implications for how doctors treat patients with heart disease, one of the leading causes of the death. While flies and humans might seem to be worlds apart evolutionarily, the two species' hearts age in a similar fashion. By middle age, cardiac muscles in both species tend to contract with less strength and regularity.

TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2

Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood.

Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control.

Healthier lifestyle choices are called healthier lifestyle choices for a reason: they do improve health over the long term. That translates to a reduced risk of suffering any of the common age-related diseases, and a noteworthy delay in their incidence when they do occur. Per the epidemiological research noted here, the difference between healthy and unhealthy lifestyles amounts to eight to ten more years of life free from the common chronic diseases of aging.

Researchers looked at 34 years of data from 73,196 women and 28 years of data from 38,366 men participating in, respectively, the Nurses' Health Study and the Health Professionals Follow-up Study. Healthy diet was defined as a high score on the Alternate Healthy Eating Index; regular exercise as at least 30 minutes per day of moderate to vigorous activity; healthy weight as a body mass index of 18.5-24.9 kg/m2; and moderate alcohol intake as up to one serving per day for women and up to two for men.

They found that women who practiced four or five of the healthy habits at age 50 lived an average of 34.4 more years free of diabetes, cardiovascular diseases, and cancer, compared to 23.7 healthy years among women who practiced none of these healthy habits. Men practicing four or five healthy habits at age 50 lived 31.1 years free of chronic disease, compared to 23.5 years among men who practiced none. Men who were current heavy smokers, and men and women with obesity, had the lowest disease-free life expectancy.

"Previous studies have found that following a healthy lifestyle improves overall life expectancy and reduces risk of chronic diseases such as diabetes, cardiovascular disease, and cancer, but few studies have looked at the effects of lifestyle factors on life expectancy free from such diseases. This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free."

Link: https://www.eurekalert.org/pub_releases/2020-01/htcs-hlh010620.php

The gut microbiome produces a range of metabolites that are beneficial to health, though this production slackens with age for reasons that are still being explored. In recent years, researchers have demonstrated in mice that the short-chain fatty acids butyrate, acetate, and propionate are produced by gut microbes and have beneficial effects on brain function, such as by improving the pace of neurogenesis. Given this, it is a reasonable proposition to think that supplementation with these compounds might incrementally improve recovery from stroke or other form of brain injury. Researchers here show that to be the case in mice, and investigate the mechanisms by which these compounds beneficially alter the behavior of cells in injured areas of the brain.

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut-brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFA), key bioactive microbial metabolites, are the missing link along the gut-brain axis and might be able to modulate recovery after experimental stroke.

SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFA induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in dendritic spine and synapse densities. RNA-sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional re-modelling. Further analyses confirmed a substantial impact of SCFA on microglial activation, which depended on the recruitment of T cells to the infarcted brain.

Previous studies have shown a bi-directional communication along the gut-brain axis after stroke. Stroke alters the gut microbiota composition, and in turn, microbiota dysbiosis has a substantial impact on stroke outcome by modulating the immune response. However, until now the mediators derived from the gut microbiome affecting the gut-immune-brain axis and the molecular mechanisms involved in this process were unknown. Here, we demonstrate that SCFA - fermentation products of the gut microbiome - are potent and pro-regenerative modulators of post-stroke neuronal plasticity at various structural levels. We identified that this effect was mediated via circulating lymphocytes on microglial activation. These results identify SCFA as a missing link along the gut-brain axis and as a potential therapeutic to improve recovery after stroke.

Link: https://doi.org/10.1523/JNEUROSCI.1359-19.2019

Clearing amyloid-β from the brain has failed to reverse Alzheimer's disease in patients, and this unfortunate outcome is slowly - all too slowly - producing a change in direction in the mainstream of Alzheimer's research. One possible conclusion is that amyloid-β is simply the wrong target, and this has led to a great deal of alternative theorizing in recent years. Even so, the consensus remains that amyloid-β does play a significant role in the condition, albeit not enough of a role in the later stages of Alzheimer's to allow anti-amyloid therapies to work. The jury remains out on whether early reduction in amyloid-β aggregation can postpone Alzheimer's - i.e. whether this aggregation actually a causative mechanism or whether it is a side-effect of the actual cause, such as chronic inflammation driven by persistent infection.

A currently popular view is that the mechanistic evidence continues to suggest that amyloid-β is important, and thus it should be targeted - but not in isolation, as the past decade or two of failed trials amply demonstrate that removal of only amyloid-β is not sufficient. The conclusion is that there must also be reductions in tau aggregation, perhaps treatment of cerebrovascular dysfunction, suppression of inflammation in the brain, and so forth. Along these lines, today's open access research is a demonstration of a combination immunotherapy in mice that targets both amyloid-β and tau. Absent stunning success in some of the more radical new directions in Alzheimer's research, such as restoring drainage of cerebrospinal fluid, we will likely see such combination immunotherapies tested in humans in the near future.

Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice

Alzheimer's disease (AD) is a complex and multifactorial disease involving genetic and environmental risk factors that together lead to the progressive accumulation of two hallmark pathologies: β-amyloid plaques and neurofibrillary tangles (NFTs). Although many clinical trials have aimed to reduce β-amyloid and, more recently, to target the accumulation of tau that drives NFT formation, debate remains regarding which of these pathologies represents the most tractable target, and the precise timing for these potential treatments.

Recent longitudinal analyses demonstrated evidence of synergism between Aβ and phosphorylated tau (p-tau) suggesting these pathologies may interact to trigger the progression from amnestic mild cognitive impairment (MCI) subjects to AD dementia. PET imaging studies suggest that Aβ deposits start decades before dementia onset, and may or may not precede tau pathology, with the latter correlating better with symptom onset and the degree of dementia.

According to the modified amyloid cascade model, primary age-related tauopathy (PART) develops universally as a function of aging and, by itself, produces no or only mild cognitive symptoms. Aβ deposition occurs independently in the neocortex and induces or facilitates the spread of pathological tau, perhaps by promoting the production of pathological tau strains. Pathological tau is directly associated with neurodegeneration, which in turn drives cognitive decline. In this model of AD, Aβ does not directly cause cognitive symptoms but is still central to disease pathogenesis as a dominant driver of downstream pathological processes including tau pathology.

This synergistic model suggests that combinatorial/multi-target therapies directed at the accumulation of both amyloid and tau pathologies may be more effective in the treatment of AD than previously tested unimodal approaches. Recently, we demonstrated that the combination of AV-1959R and AV-1980R vaccines targeting Aβ and tau, respectively, induced robust antibody responses against various forms of both Aβ and tau pathological molecules in wildtype mice.

Here, we tested the therapeutic efficacy of co-formulated vaccines targeting Aβ and tau administered simultaneously in combination with AdvaxCpG adjuvant in the Tau22/5xFAD (T5x) mouse model of AD that develops highly aggressive Aβ and tau pathology. T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of T5x mice.

Researchers here report on the use of a combination of a brain-computer interface and functional electrical stimulation of muscles to bypass damage leading to paralysis of the hand, allowing some degree of restored function. The approach was demonstrated in non-human primates in which nerves connecting the hand to the brain were damaged via surgery. Competition in approaches to the problem of nervous system damage is a good thing, but one would hope that this class of application of brain-computer interface is largely made irrelevant by future advances in regenerative medicine.

Paralysis following stroke is a leading cause of long-term motor disability. Brain machine interfaces (BMIs) can transform cortical activity into control signals for an external device, such as a robotic arm or computer cursor, and may provide a solution for restoring lost function. Bypassing the damaged pathway using brain-controlled functional electrical stimulation (FES) to regain volitional control of the paralysed limb is promising for restoring lost motor function. Brain-controlled FES works as an "artificial" neural pathway by creating a causal relationship between brain activity and an evoked limb movement. However, subjects may be required to learn a novel causal input-output relationship to control the paralysed limb.

Disruption of descending pathways, as can result from stroke, results in a lost connection between the brain and target muscles. Functional recovery in such a situation is characterised by substantial reorganisation in the structure and function of the damaged brain. Thus, our nervous system shows remarkable flexibility to adapt to novel neuromotor mappings. How the brain incorporates a novel "artificial" neural pathway into volitional limb control within the surviving cortical areas remains largely unclear.

In the present study, we generated a model of chronic hemiparalysis in the extremities caused by subcortical stroke in monkeys. We then employed an artificial cortico-muscular connection (ACMC) to connect the preserved cortical areas to muscles beyond the damaged site. Specific neural oscillations in the cortical area were detected contingent to the input and converted into electrical stimulation delivered to the muscles in real time. We demonstrated that, despite damage to subcortical areas, a flexible change in the neural oscillations controlling the ACMC was observed in a targeted manner throughout an extensive sensorimotor area. Thus, monkeys that experienced a subcortical stroke could rapidly learn to regain lost volitional control of a paralysed hand.

Link: https://doi.org/10.1038/s41467-019-12647-y

Some fraction of what we think of as cardiovascular aging is in fact due to the lack of exercise that is so very prevalent in our society of comfort and machineries of transport, rather than due to inexorable underlying processes of aging. Those processes certainly exist, and ultimately cut down even the fittest individuals, but failing to maintain fitness in later life does tend make the outcomes of aging worse. Studies of the sort noted here are a way to assess how large the burden of a lack of fitness might be, at least when it comes to cardiovascular function. The researchers took a collection of people who are training to run a marathon for the first time, and quantified the improvements that take place in cardiovascular metrics over the course of this effort.

Aging increases aortic stiffness, contributing to cardiovascular risk even in healthy individuals. Aortic stiffness is reduced through supervised training programs, but these are not easily generalizable. The purpose of this study was to determine whether real-world exercise training for a first-time marathon can reverse age-related aortic stiffening. Untrained healthy individuals underwent 6 months of training for the London Marathon.

Assessment pre-training and 2 weeks post-marathon included central (aortic) blood pressure and aortic stiffness using cardiovascular magnetic resonance distensibility. Biological "aortic age" was calculated from the baseline chronological age-stiffness relationship. Change in stiffness was assessed at the ascending aorta (Ao-A) and descending aorta at the pulmonary artery bifurcation (Ao-P) and diaphragm (Ao-D).

A total of 138 first-time marathon completers (age 21 to 69 years, 49% male) were assessed, with an estimated training schedule of 6 to 13 miles/week. At baseline, a decade of chronological aging correlated with a decrease in Ao-A, Ao-P, and Ao-D distensibility by 2.3, 1.9, and 3.1 x 10^-3 mm/Hg, respectively. Training decreased systolic and diastolic central (aortic) blood pressure by 4 mmHg and 3 mmHg. Descending aortic distensibility increased (Ao-P: 9%; Ao-D: 16%), while remaining unchanged in the Ao-A. These translated to a reduction in "aortic age" by 3.9 years and 4.0 years (Ao-P and Ao-D, respectively). Benefit was greater in older, male participants with slower running times.

Link: https://doi.org/10.1016/j.jacc.2019.10.045

There are many situations in which it might be advantageous to deliver large numbers of immune cells into a patient, to set them to work as reinforcements for the native immune cell populations. It is technically feasible to grow and then introduce into a patient twice as many - or ten times as many, or even more - of some classes of immune cell as are normally present in the body at any given time. At the moment, therapies of this nature are largely focused on treating cancers, such as the approach pioneered by LIfT Biosciences. That the transferred immune cells come from a donor rather than being generated from a sample of patient cells is actually helpful in terms of their ability to attack a cancer.

For other potential applications, however, it will usually be less helpful to have immune cells from person A introduced into person B. The downsides, in that the immune cells are foreign and can thus attack healthy tissue or spur inflammatory responses from native cells, can outweigh the benefits. Nonetheless, in the research materials noted below, scientists use this approach in the treatment of the later stages of sepsis resulting from infection. This is a life-threatening condition in which older individuals fare far worse than younger individuals. Older patients have a higher risk of sepsis, and lower odds of survival, particularly at the point at which the immune system becomes overwhelmed by a population of pathogens replicating beyond its ability to control.

In a perfect world, it would be possible to generate cost-effective populations of immune cells that can be introduced into any patient as a way to reinforce the immune response for a time. This would either mean a much cheaper approach than presently exists to the production patient-matched cells using reprogramming techniques, or a way to generate cell lines that are not recognized as being foreign to the body, no matter who they are provided to. Approaches to both of these options are at various stages of development in the research community and in biotech companies.

Finding a new way to fight late-stage sepsis

Cells called macrophages are one of the first responders in the immune system, with the job of "eating" invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal and they don't function as they should. In this study, researchers collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins.

The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to "manufacture" a new therapy.

After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant Staphylococcus aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about 4 million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours - and for those with lingering bacteria in the blood, a second treatment cleared them away.

Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis, and thus, alternative therapeutic approaches are urgently needed. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression.

The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.

There are many overlapping mechanisms involved in the age-related loss of stem cell function in muscle tissue that leads to loss of muscle mass and strength. To name a few: the mitochondrial dysfunction that occurs in all tissues, or the chronic inflammation produced by senescent cells and the aging immune system. The authors of this open access review paper choose to divide approaches to treatment of loss of muscle stem cell function, whether compensatory or actual rejuvenation, into those that affect stem cells versus those that affect the stem cell niche. Research has suggested that the fact that muscle stem cell populations become less active with age is more a matter of changes in the niche and systemic signaling rather than inherent damage to the stem cells themselves, but these changes must still originate in damage elsewhere in tissue.

Ex vivo manipulations of aged satellite cells have proven to be effective strategies to reverse some of the intrinsic alterations limiting their regenerative potential. These manipulations include genetic interventions to silence p16INK4a expression, thereby restoring quiescence and regenerative capacity to the aged satellite cell. Similarly, ex vivo pharmacological inhibition of p38 MAPK signaling decreases the expression of cell-cycle inhibitors, such as p16INK4a, and restores asymmetric division in satellite cells, contributing to enhanced regenerative potential of aged satellite cells in muscle transplantation experiments.

In vivo, local and systemic interventions have also shown promise in reversing age-related satellite cell defects. For example, systemic pharmacological treatments to restore basal autophagy flux preserved quiescence and muscle stem cell regenerative capacity in old muscles. Similarly, systemic delivery of oxytocin restores age-related regenerative capacity in old muscles, promoting satellite cell activation and proliferation, while systemic delivery of WISP1 during a regenerative event improves myogenic commitment and regenerative success. Moreover, systemic delivery of exogenous α-Klotho improves muscle stem cell bioenergetics and improves regenerative capacity in aged animals.

Rejuvenating interventions able to target the whole organism have also a positive impact on satellite cell function during aging. Successful interventions include caloric restriction, rapamycin treatment, supplementation with the NAD+ precursor nicotinamide riboside, senescent cell ablation, and in vivo reprogramming. These studies anticipate the existence of common hallmarks of aging associated with satellite cell loss of function in old animals, which can be considered common targets for intervention. Consistently, targeting chronic inflammation (a shared feature of several age-related pathologies) through systemic treatment with an inhibitor of NFκB activation improves myogenic function in aged satellite cells.

Link: https://doi.org/10.1111/febs.15182

Over longer timescales involving large-scale funding, meaningful progress only occurs in those lines of research and development that enjoy broad public support and understanding. While it is the case that small groups of philanthropists and visionaries are those who do the hard (and largely unacknowledged) work to create new possibilities, of those options, only those that are welcomed and desired by the masses are brought into reality. In the matter of rejuvenation therapies, we presently stand somewhere in an awkward transition phase in which the experts are largely convinced, but the public remains largely ignorant or skeptical. Given that the research community is resolved to build ways to treat aging as a medical condition, and a related biotech industry is forming, we'll see ever more examples of advocacy aimed at educating the public, in order to obtain support for bigger and broader programs that will advance the state of the art in this field of medicine.

It's not your imagination - the world is graying. In fact, by 2050, the global population age 65 and older is projected to nearly triple, to 1.5 billion. With this aging population, it will be more important than ever to reduce the burden of age-related disease. In the future, science will allow us to intervene in the aging process to make this a reality. It's imperative to keep our older population healthy and independent as long as possible. As this population grows, we'll need to provide help to increasing numbers of older people who are no longer independent. It will be a huge challenge for us as a society in the next 20 or 30 years.

Aging is a biological and physiological process like any other. We can learn how it works - how cells and molecules create what we see as "aging" in a person. Aging can be beautiful, but it is also the number-one risk factor or driver of most of the medical problems that we treat in adults: cancer, diabetes, dementia, Alzheimer's disease, cardiovascular disease, strokes, and heart attacks. The crazy thing is we can manipulate the aging process. We can adjust it. We can treat it. None of this is science fiction anymore. It's all science fact, right up to the part where people are conducting clinical trials of drugs that treat complex health problems through targeting molecular aging mechanisms. In geroscience, we seek to understand the relationship between aging, disease, and quality of life. The promise of this field is that by intervening in the process of aging, we could slow, prevent, delay, or reduce the risk of all sorts of diseases - all at the same time.

When visiting your primary physician in 2050, you'll have your aging mechanism risk factors checked, and you'll probably have preventive treatments. For example, we'll treat your senescent (old, inactive) cells or your autophagy (the process by which your body removes old, damaged proteins). If something is amiss in your risk factors, then we'll make adjustments. It'll just become part of regular preventive medicine.

Link: https://www.ucsf.edu/magazine/aging-optional