Fight Aging!

In today's research materials, scientists demonstrate that the combination of reduced SIRT1 and SIRT3 causes weakness in heart muscle via disruption of mitochondrial function. Mitochondria are the power plants of the cell, a herd of hundreds of bacteria-like organelles that are responsible for producing the chemical energy store molecule adenosine triphosphate (ATP) to power cellular operations. Impairment of mitochondrial function thus results in impaired cell function, a characteristic change observed in old tissues. Mitochondrial dynamics, the balance of fusion and fission of mitochondria, shift with age in ways that impair the processes of mitophagy that are responsible for removing damaged mitochondria. This leads to impaired function as damaged mitochondrial accumulate. A number of lines of evidence suggest that improved mitophagy can help restore mitochondrial function in old individuals.

Of note, the research here only shows that (a) depletion of SIRT1 and SIRT3 in young individuals causes harm, (b) the resulting changes in cells have some similarities to those seen in aging, and (c) that SIRT1 and SIRT3 are depleted in old individuals. This does not prove that boosting SIRT1 and SIRT3 in old individuals will help restore lost function, but it makes the case to fund that experiment. Of note, upregulation of SIRT1 on its own was the focus of considerable effort some years back, with entirely lackluster results when it came to health and life span. SIRT1 just does not seem to be an important part of the mechanisms linking metabolism to aging. One has to make a solid case in order to convince people to revisit that failure.

Age-related decline in two sirtuin enzymes alters mitochondrial dynamics, weakens cardiac contractions

Mitochondria produce the energy needed to drive nearly all processes in living cells. Cardiac muscle cells contain more mitochondria than any other cells, because the heart needs large amounts of energy to constantly pump blood throughout the body. Stable mitochondrial dynamics maintain a healthy balance between the constant division (fission) and merging (fusion) of mitochondria and help ensure the quality of these specialized structures known as the "powerhouse" of the cell.

Reperfusion, a common treatment following acute heart attack, restores blood flow (and thus oxygen) to a region of the heart damaged by a blood clot blocking the coronary artery. Paradoxically, in some patients this necessary revascularization procedure triggers further injury to heart muscle tissue surrounding the initial heart attack site. No effective therapies currently exist to prevent reperfusion injury.

To help analyze the response of cardiac mitochondria to ischemia-reperfusion stress, researchers deleted SIRT1 or SIRT3 in cardiac muscle cells of mouse hearts, and examined the mitochondrial response to ischemic stress by restricted blood flow. The researchers found that the mitochondria in mouse hearts lacking cardiomyocyte SIRT3 were more vulnerable to reperfusion stress than the mouse hearts with SIRT3 intact. The cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout mice physiologically resembled that of aged wildtype (normal) mice retaining cardiac SIRT3.

Furthermore, the young mice with SIRT1 or SIRT3 removed had measurably weaker cardiomyocyte contractions and exhibited aging-like heart dysfunction when ischemia-reperfusion stress was introduced. In essence, without SIRT1/SIRT3 the hearts of these otherwise healthy young mice looked and behaved like old hearts.

Alterations in mitochondrial dynamics with age-related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis, especially mitochondrial dynamics, to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury.

Providing a patient's T cells with a receptor to match the surface characteristics of the patient's cancer cells is proving to work quite well for some types of cancer. Unfortunately the match is never perfectly specific for cancerous cells, and chimeric antigen receptor T cells (CAR-T cells) can do a lot of damage to healthy tissue in many of the desired scenarios for treatment. Researchers here report on one of a number of presently explored approaches to limit the activation of CAR-T cells to only the cancerous tissue of interest, thereby making the therapy more viable.

New work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors. CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient's T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.

This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That's because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells - these effects are known as on-target, off-tumor toxicity. To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on. Ultrasound can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team's approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that's on top of the tumor to activate the CAR T cells. The transducer uses focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately - in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit) - without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.

Link: https://ucsdnews.ucsd.edu/pressrelease/ultrasound-remotely-triggers-immune-cells-to-attack-tumors-in-mice-without-toxic-side-effects

An interesting observation is discussed in this open access paper, which is that most small molecule compounds that extend life in short lived species also change the expression of extracellular matrix genes. The majority of such compounds are thought to extend life by provoking some of the same stress response mechanisms as calorie restriction, heat shock, and other common stressors, resulting in improved cell maintenance and thus improved cell and tissue function. Why do they also lead to changes in cellular activity relating to the maintenance of the extracellular matrix? A detailed answer to that question may emerge at some point, but cellular metabolism and its interaction with aging are very complex, slow-moving areas of study. Manipulation of metabolism to slow aging is a part of the field in which interventions are found by screening, none are fully understood, and none have interestingly large effects in long-lived species such as our own.

A few geroprotective drugs exist that postpone age-related diseases. For instance, the anti-diabetes drug metformin reduces age-related chronic diseases and mortality from all causes. Ongoing clinical trials on geroprotective drugs or compounds include the anti-diabetic drugs metformin and acarbose; mTOR-inhibiting and immunosuppressant drug rapamycin; natural compounds resveratrol and urolithin A; and nicotinamide adenine dinucleotide precursors NR and NMN. One primary outcome measure used in the aforementioned clinical trials for metformin and acarbose is the restoration from an "old" to a "youthful" gene expression signature. Therefore, we reasoned that cross-comparing youthful expression signatures against expression profiles elicited by small molecules could identify geroprotective compounds.

A key signature of aging is the continuous decline of collagen and cell adhesion gene expression accompanied with an increase in matrix metalloproteinase expression. Gene expression ontologies of extracellular matrix (ECM) genes have been associated with healthy aging in humans. The ECM not only embeds cells and tissues but also provides instructive cues that change cellular function and identity. For instance, placing old cells into a "young" ECM rejuvenates senescent cells or stem cells and even reprograms tumor cells. Moreover, collagen homeostasis is required and sufficient for longevity in Caenorhabditis elegans. Chondroitin biosynthesis and TGFβ pathway are frequently enriched in C. elegans longevity drug screens. Collectively, these functionally implicated genes are all members of the matrisome.

To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.

Link: https://doi.org/10.1111/acel.13441

It is suggested that inflammation in the gums spreads to cause inflammation in the heart and brain, raising the risk of cardiovascular disease and dementia. There is a good deal of evidence for this spread of inflammation to exist, the question is whether or not it contributes to age-related disease to a significant degree in comparison to other mechanisms present in the aging body. Epidemiological data such as that reported in today's open access paper shows meaningful correlations between poor oral health and raised risk of mortality, but it is only a matter of correlation. It might also be compared with other studies, such as an analysis that suggested only a small effect on risk of dementia due to gum disease.

Another possibility, when looking at large effect sizes such as those observed in the study below, is that people with poor oral health have poor oral health because they make bad lifestyle choices and fail to adequately maintain their health in a more general sense. Choose to live an unhealthy life and the gums will be far from the only part of the body to suffer as a consequence. As a further alternative, consider that those people with the worst burden of age-related damage, dysfunction, and chronic inflammation may well suffer worse oral health as one of the many outcomes. There, a raised mortality risk and a raised risk of gum disease stem from the same root causes.

Oral health and all-cause, cardiovascular disease, and respiratory mortality in older people in the UK and USA

Aging is characterized by an accumulation of chronic diseases and conditions, including poor oral health, which can influence quality of life and health. Oral health problems, including tooth loss, periodontal disease, and dry mouth, accumulate throughout adult life and worsen with increasing age3. Poor dental health is associated with high levels of inflammation, poor diet quality, and conditions such as disability, diabetes, and increased risk of cardiovascular disease (CVD) and pneumonia.

Furthermore, studies have suggested that poor oral health is associated with higher risk of mortality, including major causes of death such as CVD and respiratory diseases or infections. Tooth loss and periodontal disease have been reported to be associated with increased risks of all-cause, CVD, and respiratory mortality in community-dwelling middle-aged and older people. Furthermore, poor self-rated oral health was found to be associated with increased risk of all-cause mortality in a population of middle-aged and older adults.

We used cohort data from the British Regional Health Study (BRHS) (N = 2147, 71-92 years), and the US Health, Aging, and Body Composition (HABC) Study (N = 3075, 71-80 years). Follow-up was 9 years (BRHS) and 15 years (HABC Study). Oral health comprised tooth loss, periodontal disease, dry mouth, and self-rated oral health. Cox regression was performed for all-cause mortality, competing risks for CVD mortality, and accelerated failure time models for respiratory mortality.

In the BRHS, tooth loss was associated with all-cause mortality (hazard ratio = 1.59). In the HABC Study, tooth loss, dry mouth, and having ≥ 3 oral problems were associated with all-cause mortality; periodontal disease was associated with increased CVD mortality (subdistribution hazard ratio = 1.49); tooth loss, and accumulation of oral problems were associated with high respiratory mortality (time ratio = 0.73). Findings suggest that poor oral health is associated with mortality.

Genflow Biosciences is working on a gene therapy to deliver a variant SIRT6, a protein involved in DNA repair, and thus touches on many aspects of aging. Upregulation of SIRT6 modestly extends life in mice, accompanied by what looks like a better maintenance of mitochondrial function into old age. Versions of SIRT6 found in short-lived mammalian species appear to produce a worse efficiency of DNA repair than the version found in long-lived mammalian species.

The Genflow principals intend to deliver a SIRT6 gene therapy as a compensatory approach to DNA repair deficiency conditions, such as Werner syndrome, that have the appearance of accelerated aging. This is hoped to be a stepping stone to later attempts to treat aging. It remains an interesting question as to what adjustments to DNA repair efficiency can do for long term health in long-lived mammalian species such as our own. Is this yet another case, like stress response upregulation, in which modest effect sizes in mice turn into negligible effect sizes in humans? The only practical way to find out is to try.

Key to Genflow's approach is a collaboration with Vera Gorbunova - a member of the company's scientific advisory board, and well known for her research into SIRT6. "In 2019, Vera published a paper that showed, in rodents, you could have a very good correlation between lifespan and the quality of SIRT6. She found she could increase or decrease the lifespan of rodents based on the variant of SIRT6 that she was providing." This led researchers wonder whether it was possible to find a "better" SIRT6 than the one that already exists in humans. "We discovered that it was possible, thanks to the discovery of a variant of SIRT6 only found in centenarians. So we decided to create a company that will deliver this SIRT6 variant in order to prevent the accelerated aging process."

"Ten years ago, gene therapy was a bad word associated with high cost and high toxicity - a dangerous last resort therapy. Now you see progress in AAVs every week. Today we have AAVs that are almost invisible to the immune system, they are non-integrating, their cost has decreased substantially, and there are now more than 40 companies developing clinical trials with AAVs. So, it's now possible to have an ethical, patient friendly and cost-effective intervention at the genetic level."

While progeria, Werner's syndrome, and other indications are in the company's pipeline for eventual human trials, Genflow is really only thinking about targeting aging. "One of the differences between us and other longevity companies is that we are fully dedicating to longevity. Yes, we will have a trial in Werner's syndrome, but we consider that a door opener to having a true aging indication. At one point, we know that the regulatory agencies will change their mindset on this - we see an evolution - and we want to be positioned to be to take advantage of that."

Link: https://www.longevity.technology/gene-therapy-uses-sirt6-variant-found-in-centenarians/

People who survive to exceptional old age tend to do so because they have a lower burden of damage and dysfunction. A lesser degree of chronic inflammation maintained over time, for example, improves the long-term function of organs throughout the body. That in turn leads to a lesser degree of age-related disease and the lower mortality rate needed in order to survive to exceptional old age. Thanks to variations in lifestyle and burden of persistent infection, one can find groups with better health than average, such as the nonagenarians noted here, who collectively exhibit a significantly lower risk of fracture due to weakened bone strength. As to why they are better off, that question is left unanswered by the authors of this paper. It is interesting to note the metrics that were not different, such weight and common blood markers associated with bone health.

The goal of this study was to investigate whether various aspects of bone health among the very elderly could provide insight into the aging process in this unique population. Our study investigated the prominence of fractures, osteopenia, and osteoporosis among our study population and made comparative analyses specifically looking at metabolic values and blood indices characteristic of bone health as well as the impact of prescribed medication therapies.

Overall, we found a low rate of fractures in our group of patients over 90 years of age. The distribution of fractures found in our study correlates with the expected distribution of fractures for an elderly cohort, with the most common occurring at the spine and hip. Additionally, there was a trend toward lower incidence of fracture among the oldest individuals, as compared to the general very old population in the United States. The incidence for hip fractures in the ≥100-year-old population has been estimated to be 23.1 per 1000 individuals per year (2.3% per year), whereas our study found a fracture incidence of 1.9% per year among our population of very elderly individuals. This indicates that our population of nonagenarians may have characteristics that contributed to the preservation of bone health even into extreme old age.

In conclusion, patients over 90 years of age had an overall low prevalence of fractures and relative preservation of bone health, suggesting a preserved bone molecular profile in these individuals. Epigenetic factors and activity levels might also have favorably affected bone health. The low percentage of osteoporosis and fractures likely reduced the morbidity and mortality in this population, potentially contributing to their overall longevity.

Link: https://doi.org/10.1177%2F21514593211036231

Survival to 100 years of age is a rarity at the present time, but if the present slow upward trend in life expectancy continues, most people born today will live to 100 or more. That trend will, of course, not continue as-is. The past trend was due to incidental effects of public health measures and general progress in medicine on the mechanisms of aging. The trend in life expectancy will leap upwards with the advent of rejuvenation therapies that deliberately target the reversal and repair of those mechanisms. But that is a topic for another post.

Here, let us focus on what actually happens at the present time to people in the last stages of aging. I think it is important to look at the reality of the situation, as in some circles, centenarians are held up as exemplars of health in later life, and the goal of medicine put forward as upholding the slow trend of increased life expectancy, thereby enabling more people to follow the same path. This is a terrible goal. Centenarian health is not good. As today's open access paper shows, near all centenarians are frail. Frailty is a life-limiting set of circumstances, caused by a high burden of the cell and tissue damage that lies at the root of aging. Frailty manifests as physical weakness, dependency, vulnerability to infection, cognitive decline, and a high mortality rate. No-one would choose to be frail, given the option. Mere survival should not be held up as an exemplar of health.

The goal of developing rejuvenation therapies is maintenance of health, the elimination of suffering and limitations such as frailty, cancer, cardiovascular disease, and so forth. Increased healthy life span, ultimately far beyond present human capabilities, will be a happy side-effect of keeping the human machine in good running condition. Rejuvenation is just another name for preventative maintenance sufficient for good operation: identify the damage that limits capabilities, and remove it before it causes major breakage. That is a lot more complicated in a mammal than it is in a car, but the concept is the same, and it will work just as well. If the entire field of longevity science turns into low-expectation-value efforts to modestly slow aging with the goal of making more frail centenarians, then we will have missed the point of the exercise, and missed the opportunity to achieve a great advance in the quality of life for all of humanity.

Age- and Gender-Specific Prevalence of Frailty and Its Outcomes in the Longevous Population: The Chinese Longitudinal Healthy Longevity Study

Based on the Chinese Longitudinal Healthy Longevity Study (CLHLS, 2008-2018), individuals aged ≥ 65 years having complete data of frailty were recruited. The present study reported the prevalence of pre-frailty and frailty among the population with a mean age of 85 years, which were 54.1 and 26.3%, respectively. Females were predominant among frail population in all age groups whereas males were dominant among pre-frail individuals aged ≥ 80 years. Both pre-frailty and frailty were strongly associated with multiple adverse outcomes. Males and the young-old (younger than 80 years) were the most susceptible to the risk of mortality.

Healthy aging is an important goal of the public health in the 21st century. However, a huge gap exists between longer life and healthy aging. The present study indicated the high prevalence of pre-frailty and frailty among the Chinese longevous population, which is consistent with the results from 1,253 centenarians in the 5-COOP study countries (Japan, France, Switzerland, Sweden, and Denmark). It demonstrated that the heavy burden of frailty among the longevous population was globally substantial. Notably, only 5% of centenarians and 11.1% of nonagenarians were non-frailty in the present study. Similar results were observed among centenarians in the 5-COOP countries.

Additionally, the present results comprehensively demonstrated the association between pre-frailty, frailty, and the risk of multiple adverse outcomes. It implies not only the high consumption of healthcare resources of the frail elderly, but also the suffering of patients themselves. Hence, the epidemic of frailty could be considered as one of the great barriers of healthy aging.

Near everyone in the wealthier parts of the world should undertake more physical activity than is presently the case. Too little exercise is harmful. That these populations are largely sedentary makes exercise look like a good intervention, one that improves long-term health considerably. Really, however, that exercise what is needed to bring human health up to par from its present low ebb. We evolved in an environment that required a great deal of physical activity, and many of our critical systems of regulation, maintenance, and stress response are tied to signals that are induced by physical activity. As a result, we corrode into age-related degeneration that much more rapidly in the absence of frequent, sustained exertion.

Aging is the biggest risk factor for cognitive impairment and dementia. Aerobic physical activity may improve cognitive functioning, thus delaying aging-related cognitive decline. The purpose of this review was to examine the effect of aerobic physical activity on memory and executive function in sedentary adults with no known cognitive impairment.

Databases were systematically searched for peer-reviewed articles. Randomized controlled trials of sedentary adults, aged 50 and older, that compared an aerobic physical activity intervention to either no treatment or alternative active comparator and reported outcome measures of memory and/or executive function were included. A random effects meta-analysis was performed to examine the separate effect sizes for memory and executive function.

Nine studies met inclusion criteria and contributed either memory and/or executive function effect sizes (n = 547). Results from the random effects meta-analysis suggested, by post-intervention, a large effect size for the aerobic physical activity interventions on memory and a small effect on executive function. Aerobic physical activity may improve memory and executive function in sedentary adults without cognitive impairment. Policymakers and providers should promote aerobic physical activity in this population, and further research should investigate the most effective ways to promote aerobic physical activity in mid-life to older adults.

Link: https://doi.org/10.1016/j.pmedr.2021.101496

Misfolding and aggregation of amyloid-β in the brain is thought to be the initial cause of mild cognitive impairment that leads into Alzheimer's disease. In recent years, this hypothesis has been challenged as clearance of aggregates via immunotherapy has failed to produce improvements in patient outcomes. This may be because the extracellular aggregates are a side-effect and the real harms conducted by amyloid-β occur elsewhere, inside cells. Or it may be that amyloid-β aggregation is a side effect, and other mechanisms such as chronic inflammation and chronic infection are the real drivers of Alzheimer's disease. Nonetheless, mechanistic evidence continues to link amyloid-β with pathology, such as the degeneration of synapses.

In brain disorders such as Alzheimer's, synaptic connections, which hold our precious memories, are known to break down too early and disappear. This synapse degeneration is thought to start long before the loss of memory and accelerate as diseases progress. The causes of synapse degeneration in neurodegenerative disorders has not been well understood, mainly because scientists have not yet unraveled the key mechanisms that normally hold together these tiny structures. Researchers have now identified the main components driving amyloid beta-associated synapse degeneration. Amyloid beta are peptides of 36-43 amino acids derived from the amyloid precursor protein (APP) and are the main component of amyloid plaques found in the brains of people with Alzheimer's disease.

Glutamatergic synapses are highly polarized structures with a presynaptic part from one nerve cell and a postsynaptic part from another. This type of polarity ensures the proper direction of information flow. Researchers had previously found that during brain development the highly polarized synaptic structures are assembled by components of the planar cell polarity (PCP) pathway: a powerful signaling pathway that polarizes cell-cell junctions along the tissue plane. Using super resolution microscopy, the researchers detected the precise location of these same PCP signaling components, called Celsr3, Frizzled3, and Vangl2, in the glutamatergic synapses in the adult brain. They then found that removing these components, essential for the initial assembly of synapses from adult neurons, can dramatically alter the number of synapses. These surprising discoveries suggest that the overall synapse number in a normal brain is maintained by a fine balance between Celsr3 (which stabilizes synapse) and Vangl2 (which disassembles synapses).

Curious about whether these components are involved in synapse degeneration, reserachers tested whether amyloid beta, a key driver of synapse loss in Alzheimer's disease, affects the function or interaction of these proteins. In a series of experiments, they showed that amyloid beta oligomers bind to Celsr3 and allow Vangl2 to more effectively disassemble synapses, likely by weakening the interactions between Celsr3 and Frizzled3. Ryk, a regulator of the PCP pathway that interacts with Frizzled3 and Vangl2, is also found present in the adult synapses and functions in the same way as Vangl2 to mediate synapse disassembly. Blocking Ryk using function-blocking antibodies can protect synapses from amyloid beta-induced degeneration.

The researchers then used 5XFAD mice, a well-known mouse model of amyloid beta pathology. This transgenic mouse carries five human mutations that cause Alzheimer's disease and therefore shows severe symptoms of synapse degeneration and cognitive function loss. They found that removing Ryk by gene knockout from adult neurons protected synapses and preserved cognitive function of 5XFAD mice. Infusion of the function blocking the Ryk antibody also protected synapses and preserved cognitive function in 5XFAD mice, suggesting the Ryk antibody is a potential therapeutic agent.

Link: https://ucsdnews.ucsd.edu/pressrelease/uc-san-diego-researchers-discover-key-mechanisms-behind-synapse-degeneration-in-alzheimers-brain

First generation stem cell therapies are simple in concept, a matter of transplanting cells taken from person A into person B in the hope of producing benefits, but the implementation hides a great deal of complexity. Tissue is provided by donors, cells are selected from that tissue, the resulting population of cells is expanded in culture, their behavior and state may be modified in simple ways via the addition of factors, the cells are manufactured into doses that can be frozen, and then injected into patients. For every one of those steps there are many, many different approaches, refinements, and epicycles.

It remains poorly understood as to why the outcomes of this class of therapy are so variable, even for clinics practicing what seem to be similar methodologies. It is hard to say why the (allegedly) more successful implementations are in fact more successful, particularly since most of them are owned by individual clinics and will never be the subject of formal clinical trials.

Near all such stem cell transplants reliably reduce chronic inflammation. This, at least, is fairly consistent across approaches. This outcome occurs due to signaling by the transplanted cells, and can last for months. The cells themselves near all die much more rapidly than that, though it is the case that a few clinics and approaches claim a meaningful degree of cell engraftment and survival. Beyond reductions in chronic inflammation, lasting improvement in tissue function or a regeneration of damaged tissue is a goal, but not one that is reliably achieved, considering this field as a whole.

A reduction in chronic inflammation makes age-related frailty an attractive target for stem cell therapies, characterized as it is by systemic inflammation. There is a great deal of evidence for continual inflammation to be an important cause of loss of muscle mass and strength, as well as the disruption of function in many other tissues. Thus a number of groups have attempted the expensive process of formalizing a stem cell therapy implementation in order to take it into clinical trials to treat frailty. Today's example appears modestly successful, though it is always worth comparing the outcomes of this sort of study with those that have been achieved via structured exercise programs and strength training regimens designed for the elderly.

Longeveron Announces Topline Results of Phase 2b Study of Lomecel-B for Aging Frailty

Longeveron, a clinical stage biotechnology company developing cellular therapies for chronic aging-related and life-threatening conditions, today announced results from the Company's Phase 2b trial titled: A Phase 2b, Randomized, Blinded and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B Infusion in Patients With Aging Frailty (the "Phase 2b trial"). Lomecel-B is a proprietary allogeneic product comprised of medicinal signaling cells (MSCs) from the bone marrow of adult donors and culture-expanded in Longeveron's current good manufacturing practice (cGMP) cell processing facility. The Phase 2b trial evaluated the safety and efficacy of a single peripheral intravenous infusion of four different doses of Lomecel-B cell therapy: 25 million (n=37), 50 million (n=31), 100 million (n=34) and 200 million (n=16) cells. Results were compared to placebo (n=30), on signs and symptoms of Aging Frailty, including mobility and exercise tolerance.

The main inclusion criteria for entry into the trial were subjects 70-85 years of age, a screening 6 minute timed walk distance of between 200 to 400 meters, a Canadian Health and Safety Assessment (CHSA) Clinical Frailty Scale score of 5 (mildly frail) to 6 (moderately frail), and a minimum serum TNF-α of ≥ 2.5 pg/mL. The primary analysis compared the change from baseline in six minute timed walk distance for the four Lomecel-B cohorts to the placebo cohort at Day 180. There were statistically significant increases in the highest 3 doses and no significant changes in the placebo or lowest dose of Lomecel-B (the following increases in 6 minute timed walk distance were observed: 25 million = 7.8 meters; 50 million = 35.8 meters; 100 million = 24.9 meters; 200 million= 49.3 meters; placebo = 8.0 meters).

"Improving physical function in older adults with frailty is one of the primary goals in geriatric medicine. The fact that patients enrolled in this study, with an average age of 75 and with clear mobility limitations, showed 6-month and 9-month placebo-adjusted increases in walking distance of 40 meters and 63 meters, respectively (at the 200 million cell dose), is significant for a number of reasons. Frailty is associated with poor clinical outcomes and high healthcare utilization and being able to improve and extend walking distance suggests preservation of function and potentially independence."

Much of this paper is taken up with a consideration of osteopontin in macular degeneration, but the authors also note that ostopontin levels in blood plasma are higher in older individuals. This may be connected to increased production in the vasculature, associated with rising levels of chronic inflammation in later life. Past work has also shown that osteopontin levels decline in bone marrow tissue with age, and that this is connected to the dysfunction of the hematopoietic system responsible for generating immune cells. Nothing is simple in the biochemistry of aging.

A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer's disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics.

We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina.

Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.

Link: https://doi.org/10.1038/s41379-021-00887-7

Researchers here provide evidence from human blood samples that supports a role for vascular inflammation in age-related neurodegeneration. It is becoming clear that a great deal of tissue-specific information can be harvested from extracellular vesicles present in the bloodstream, if their contents were only better mapped and understood. The research community is still quite early in the process of establishing the necessary knowledge, but proof of concept demonstrations such as the study noted here are now emerging on a regular basis.

Cerebrovascular disease and the associated blood-brain barrier (BBB) dysfunction are intimately associated with immune activation and among the most common age-associated, inflammation-mediated, degenerative brain changes. Vascular pathways are emerging as an important contributor to neurodegenerative disorders. Importantly, immuno-vascular dysregulation can cause pathology in early disease states, prior to frank brain degeneration and clinical manifestations such as mild cognitive impairment. More recently, molecular pathways are emerging to suggest a feed-forward degenerative-inflammatory phenomenon between endothelial cells, innate immune activation, and degenerative myelin debris. Therefore, identification of molecular biomarkers of immuno-vascular disease in preclinical states has important therapeutic implications for extension of health span, treatment of vascular cognitive impairment.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition, and neuroimaging were calculated via regression modelling.

EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components.

These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

Link: https://doi.org/10.1038/s41598-021-91759-2

The pace of age-related loss of function and consequent mortality accelerates over time, picking up particularly rapidly in later life. This is characteristic of systems in which multiple processes feed into each other. A causes B, but B also makes A worse. In the biology of aging there are many more than two processes at work, but the authors of today's open access paper picked two areas of aging in order to examine their bidirectional relationship. Firstly the accumulation of senescent cells, and secondly immunosenescence, the age-related decline of immune system function.

Cells become senescent constantly in the body, largely as a result of somatic cells reaching the Hayflick limit on replication. Wound healing, potentially cancerous molecular damage, and the signaling of other senescent cells are also relevant causes of cellular senescence. Some senescent cells self-destruct, while others are destroyed by the immune system. That immune surveillance of senescent cells becomes slower and less effective as the immune system falls into immunosenescence in later life, allowing for senescent cell accumulation.

Equally, senescent cells secrete inflammatory, disruptive signaling that causes chronic inflammation as well as harmful changes in cell behavior in the hematopoietic system responsible for generating new immune cells. Inflammation also contributes to the involution of the thymus, where T cells mature, accelerating the decline of adaptive immune function by reducing the supply of new T cells. Further, immune cells themselves become senescent in increasing numbers, a response to the burden of too much cell replication and too few replacement cells.

It is plausible that these mechanisms indicate that the progression towards immunosenescence leads the accumulation of senescent cells in the early dance of cause and effect in mid-life, before everything in the body becomes so broken that it is hard to say what is most responsible. It is very hard to assign appropriate blame to interacting mechanisms of aging without a way to eliminate one of them at a time and observe the results, however. Intuition is rarely useful. With the advent of senolytic therapies to clear senescent cells, it should be possible to say with certainty at some point as to whether immunosenescence is upstream of cellular senescence in aging. Few researchers are looking at the details of cellular senescence or immune system decline at early stages in the aging process, however.

Cellular senescence in lymphoid organs and immunosenescence

The immune system is a complex network of cells and tissues working in coalition to maintain the health of an organism. It not only clears foreign pathogens, but also helps to maintain the integrity of the organism by clearing away dead or dysfunctional cells. Like any other system, the immune system changes with age and experiences gradual deterioration. Improving our understanding of this phenomenon is of great significance. Aging of the immune system is also one of the major factors that accelerates the deterioration of an organism, as its dysfunction not only fails to elicit a strong immune response against invading pathogens but also drives the accumulation of undesirable and malfunctioning cells.

From an evolutionary perspective, cellular senescence is widely considered to be a protective mechanism to prevent stressed and damaged cells from becoming deleterious to the body. Like most things optimized by evolution, cellular senescence is not of much concern to the younger body capable of reproduction while the older body, past its reproductive prime, is adversely affected by it. The fitness benefits that cellular senescence provides to younger, reproductively active animals, such as preventing cancer, mitigating the progression of fibrosis, and promoting optimal wound healing, have helped the phenomenon survive the arduous tests of natural selection over the millennia. Unfortunately, in almost an antagonistically pleiotropic manner, accumulation of senesent cells (SnCs) is very detrimental to the older body. Specifically, SnCs secrete various factors classified together as the senescence-associated secretory phenotype (SASP) which cause instability and dysfunction in their surrounding environment.

The interactions between SnCs and the immune system run in both directions, with the immune system surveilling and clearing the SnCs; while the SnCs frequently impede the function, and in some contexts, generation of immune cells. In young and healthy individuals, the immune system can rapidly clear SnCs after their induction, which prevents them from significantly accumulating and causing adverse effects. In older individuals, this turnover is slow and leads to the accumulation of SnCs. It has been demonstrated that accumulation of SnCs is accelerated upon impaired immune surveillance. Since advancing age is associated with impairment in immune function, the decline in the turnover of SnCs with age can, at least partially, be attributed to this impediment. Despite multiple studies demonstrating various mechanisms via which SnCs could evade immune clearance, the impact of aging on immune evasion of SnCs is not yet completely understood.

Of note, SnCs have been shown to cause stem cell exhaustion, and dysfunction. This is of great relevance and importance to the topic of immunosenescence because senescence, exhaustion, and dysfunction of hematopoietic stem cells (HSCs) causes myeloid skewing and a decrease in the production of immune cells which may be one of the underlying causes of age-related immunosenescence. However, even at an organ level, the age-associated changes that contribute to immunosenescence are multifaceted with a wide variety of undesirable phenotypic manifestations. Thus, it would be ill-advised to address each of these problems individually. A more feasible and effective way to deal with immunosenescence would be to tackle the fundamental aspects of aging that drive immunosenescence. With studies showing that clearing SnCs can rejuvenate entire tissues and organs of the aged immune system, cellular senescence is certainly one such fundamental aspect, which has the potential to address immunosenescence.

Stem cells support the maintenance of tissue by delivering a regular supply of daughter somatic cells to replace losses. Different tissues turn over at different rates, but the contribution of stem cells is vital. Stem cell function declines with age, however, and a slow spiral into frailty and organ failure follows as a consequence. In the most studied populations, this loss of stem cell function is largely a matter of declining activity in response to the age-damaged environment. Put into a youthful environment, stem cells from old tissues can still perform well.

Researchers here draw a line between declining mitophagy and declining stem cell function. Mitophagy is the specialized form of autophagy that removes damaged mitochondria in cells. Mitophagy falters in cells in old tissue due to a range of complicated issues that appear quite distant from the root causes of aging. Necessary proteins are produced in too low an amount, mitochondrial dynamics change, and the component parts of the autophagic system all suffer their own similar problems. Dysfunctional mitophagy leads to dysfunctional mitochondria, and that in turn has a negative impact on stem cell activity.

Mitophagy is a specific autophagic phenomenon in which damaged or redundant mitochondria are selectively cleared by autophagic lysosomes. A decrease in mitophagy can accelerate the aging process. Mitophagy is related to health and longevity and is the key to protecting stem cells from metabolic stress damage. Mitophagy decreases the metabolic level of stem cells by clearing active mitochondria, so mitophagy is becoming increasingly necessary to maintain the regenerative capacity of old stem cells.

Stem cell senescence is the core problem of tissue aging, and tissue aging occurs not only in stem cells but also in transport amplifying cell chambers and the stem cell environment. The loss of the autophagic ability of stem cells can cause the accumulation of mitochondria and the activation of the metabolic state as well as damage the self-renewal ability and regeneration potential of stem cells. However, the claim remains controversial.

Mitophagy is an important survival strategy against nutrient deficiency and starvation, and mitochondrial function and integrity may affect the viability, proliferation, and differentiation potential, and longevity of normal stem cells. Mitophagy can affect the health and longevity of the human body, so the number of studies in this field has increased, but the mechanism by which mitophagy participates in stem cell development is still not fully understood.

Link: https://doi.org/10.1186/s13287-021-02520-5

Aggregates of misfolded amyloid-β outside cells are linked to the development of Alzheimer's disease. The failure of immunotherapies that clear those aggregates to achieve meaningful patient benefits indicates that the original form of the amyloid cascade hypothesis of Alzheimer's disease is not correct, however. It has been suggested of late that the aggregates are important because they represent a depletion of soluble amyloid-β, and thus they are the wrong target. An alternative view, described here, is that the prion-like spread of misfolded amyloid-β inside cells is the important issue, and the external aggregates only contribute to a worsening of that problem, rather than being the primary issue themselves.

An experimental study has revealed that the Alzheimer's protein amyloid-beta accumulates inside nerve cells, and that the misfolded protein may then spread from cell to cell via axons. This happens at an earlier stage than the formation of amyloid-beta plaques in the brain, something that is associated with the progression of Alzheimer's disease. The study in question builds on previous research based on amyloid-beta's prion-like properties. This means that the protein adopts a misfolded form that acts as a template for spreading in the brain, where it accumulates and develops plaques.

"The plaques of amyloid-beta outside the nerve cells have long been a target for treatment of Alzheimer's disease. But as treatments to remove plaque have not helped against dementia, we must develop and investigate other hypotheses in order to find other targets for treatment. Our results indicate that amyloid-beta is highly relevant, but that we must focus on misfolded amyloid-beta inside the nerve cells that arise far earlier than the visible plaques."

"The increased amyloid-beta caused by misfolded amyloid-beta inside cells can bring about a vicious circle of more and more amyloid-beta production. This could explain the enormous amounts of amyloid-beta that accumulate in the brain of Alzheimer's patients. However, our results indicate that many of amyloid-beta's damaging effects may be caused by what is happening within the cells, independent of plaques. This may explain why so many experimental treatments targeting plaques outside the nerve cells have failed and that we should focus our attention inwards."

Link: https://www.lunduniversity.lu.se/article/does-alzheimers-disease-start-inside-nerve-cells

The classification of "geroprotector" is fairly recent. In present use, it largely means a small molecule drug that can favorably target mechanisms known to be associated with aging. Some of these small molecules come with evidence for a slowing of aging in animal studies. A very few can boast evidence for the same from human trials. Most geroprotectors target stress response mechanisms, those involved in calorie restriction, but senotherapeutic drugs that reduce the burden of cellular senescence might also be classed as geroprotectors.

That a drug can be called geroprotective is no guarantee that it is actually useful, of course. Effect size matters! Aspirin can reasonably be classified as a calorie restriction mimetic drug, and there is evidence for reduced mortality in old people that is mixed but better than that for most putative geroprotectors. We all know that aspirin isn't going to help us change the shape of a human life to any meaningful degree, and most geroprotectors are probably worse than aspirin in terms of reliability and size of effect. Just because a mechanism can be linked to a small molecule doesn't mean that the outcome in human medicine will be anything to write home about.

Nonetheless, given the new classification of geroprotector, there are now growing databases of actual and potential geroprotectors, assembled from the literature where there is any evidence for interaction with areas of metabolism connected to aging, or animal or human data for signs of slowed aspects of aging. Some of the many drugs that have interested researchers in connection with aging, from time to time over the past century or more, coming and going as fashionable targets for scientific programs, can now be declared potential geroprotectors. Any specific case usually provides at least some interesting insight into just how slow and lengthy is the path to understanding any given drug, and how challenging it is to assess modest effect sizes in the matter of aging.

Procaine - The Controversial Geroprotector Candidate: New Insights Regarding Its Molecular and Cellular Effects

Procaine was synthesized in 1905 and introduced in clinical practice as Novocain, soon becoming a local anesthetic prototype. Around the 1950s, a large number of accumulated data emphasized the surprising diversity of nonanesthetic effects exerted by procaine, which came to the attention of various medical research schools in Eastern and Western Europe, many doctors exploring, regardless of borders, the beneficial properties of procaine. Between 1946 and 1956 researchers described a significant number of procaine beneficial actions exerted on cellular functions and metabolism, following long-term treatment in low doses, highlighting its "rejuvenating" effects, and developed Gerovital H3 (GH3) - an original procaine-based pharmaceutical formulation. Due to these findings, procaine which was known only for its anesthetic properties became one of the most disputed medical developments of the sixties and seventies in the field of "anti-aging" therapies.

Recent progresses in the field of aging research led to the development of a new class of drugs - geroprotectors, with the ability to target fundamental mechanisms of aging common to multiple age-related diseases, such as response to oxidative damage, inflammation, hypermethylation, cellular senescence, and autophagy. Researchers have established the first public database of geroprotectors that indexes the most relevant experiments involving over 200 well-established geroprotectors or possible candidates that could extend the healthy lifespan and repair or reduce aging-related damage in model organisms.

As primary selection criteria for the potential geroprotectors, the following characteristics were recognized: (1) the ability to increase lifespan; (2) the capacity to ameliorate molecular, cellular, and physiological biomarkers to a younger state or slow the progression of age-related change of these markers; (3) a therapeutic lifespan-extending dose of geroprotector, which should be several orders of magnitude less than the toxic dose; and (4) the capacity to improve the health-related quality of life of the patient, from a physical, mental, emotional, and social viewpoint. The compliance of procaine with most of these criteria would allow it to be a potential "geroprotector" candidate.

Although GH3 was internationally launched in 1956, simultaneously with the development of the Free Radical Theory of Aging, the study of the antioxidant action of procaine and GH3 was documented only after 1980, in various experimental designs, which proved its capacity of limiting the generation of reactive oxygen species (ROS) and lipid peroxidation. Besides its antioxidant, cytoprotective, anti-inflammatory, and antiatherogenic effects, at cellular and molecular levels, procaine has multiple targets, supporting a large number of potential "geroprotective" effects. Older and more recent data revealed that procaine and its metabolites modulate several biochemical and cellular processes like mitochondrial structure and function.

Calorie restriction is the most studied means to slow aging, and from this numerous lines of work have emerged, each focused on one small subset of the sweeping changes in metabolism that occur in response to a lowered intake of nutrition. Lack of nutrients puts stress on cells and organisms, and this has been the case since the emergence of life. The response to calorie restriction thus has ancient evolutionary origins, and is quite similar across all eukaryotic species investigated to date. The one big difference is that maximum life span is greatly extended in short-lived species, but not in long-lived species such as our own. Why this is the case is a matter still under investigation, and an interesting scientific puzzle, given that so many of the short-term benefits of calorie restriction are more or less the same in mice and humans.

Among the multiple alterations that have a profound impact on aging, the nutrient sensing cell pathways have recently captured much interest thanks to their potential as therapeutic targets in the prevention of age-related diseases, and the extension of the healthy life-span. The nutrient sensing pathways are mainly regrouped in the IGF (insulin-like growth factor)/insulin, the TOR (target of rapamycin), and the AMPK (AMP-Activated Protein Kinase) pathways. Data from different experimental models have largely demonstrated that the mutations that induce life-span extension are associated with an altered activity of the above-listed signaling pathways.

Interestingly, the extension of the life-span upon inhibition of the nutrient sensing signaling pathways, has also been associated to the physiological condition induced by calorie restriction (CR). Actually, CR, which consists of the reduction in the caloric intake without malnutrition, has been reported as a robust intervention to promote life-span elongation and healthy aging in rodents at the beginning of last century, and has been further suggested to have similar effects in humans. CR regimens have been shown to induce metabolic adaptations, such as reduced oxidative stress and improved inflammatory response, that ultimately result in better life- and health-spans. Studies performed on experimental models allowed to attribute the life prolongation effects to the modulation of the IGF-1, TOR, and AMPK signaling pathways, but also to other targets, such as FOXO that stimulates protein synthesis and NfkappaB, which is involved in the inflammatory response.

Nowadays, the search for the effects of long-term lifestyle interventions initiated in early adulthood and carried on throughout the entire life captures much attention, due to the evidence that in some tissues and organs, such as the skeletal muscle, the functional decline can begin in adulthood. This interest has prompted several observational studies to understand the correlation between nutrition and health-span, and the potential of CR regimens and CR mimetics in improving the health-span of aging people. At date, there is also a large number of studies aimed at directly testing CR regimens and CR-mimetics, but there are still some shadows on their efficacy, because the time and the interval of the intervention, the variability among individuals, and other factors can compromise their effectiveness.

Link: https://doi.org/10.3390/nu13072346

It is not surprising to find data showing that a poor diet and lack of exercise correlated with an increased risk of later neurodegeneration and dementia. Plenty of studies exist to note that correlation. The question is the degree to which it is correlation versus causation. There are good reasons to believe that regular exercise slows the onset of neurodegeneration, quite clear mechanistic links that are demonstrated to be causal in animal studies. Equally, a poor diet and lack of exercise correlate with many other potential contributing factors in human populations, not least of which is frailty and other manifestations of aging. So to what degree do these correlations in human data reflect protective effects versus the tendency of those who are most affected by aging, and therefore most likely to decline more rapidly, to eat poorly and exercise little?

New research has found that both diet and exercise can influence the risk of cognitive decline (CD) and dementia by potentially influencing hippocampal neurogenesis long before their onset. The investigation studied how the blood of participants with and without CD and dementia could influence hippocampal neurogenesis in laboratory settings and whether diet and exercise were important factors. Specifically, blood samples of 418 French adults over the age of 65 were collected 12-years prior to CD and dementia diagnosis and tested on human hippocampal stem cells. Additionally, information on each participant's sociodemographic, lifestyle, and clinical data were collected and incidence cognition status and dementia were measured every 2 to 3 years over a 12-year period.

Over the course of the study, the researchers established that 12 years prior to diagnosis, both CD and Alzheimer's were associated with levels of neural stem cell death. The team also found that exercise, nutrition, vitamin D levels, carotenoid and lipid levels are all associated with the rate at which cells die off. Furthermore, physical activity and nutrition were key factors that then also determined CD status. Specifically, researchers found that reduced physical activity and increased malnutrition both increased cell death which in turn increased the risk for future CD.

While previous studies have established that diet and exercise have some protective effects against CD and dementia, these roles have been poorly understood at the neurobiological level. To date, studies on animals have shown how diet and exercise can directly influence hippocampal neurogenesis, potentially explaining how exercise and diet may biologically exert their effects, but this study sheds further light on this in the context of a human model. "If an individual displays an increase in their levels of cell death during differentiation (when neural stem cells are becoming neurons), we can look at this as a potential warning sign of CD. Conversely, a decrease in levels of cell death during proliferation (the process by which a single cell divides into a pair) and reduced hippocampal progenitor cell integrity could be viewed as a predictor for Alzheimer's disease and vascular dementia, respectively."

Link: https://www.kcl.ac.uk/news/lack-of-exercise-and-poor-nutrition-could-increase-the-risk-of-diseases-like-dementia

Most of what to my eyes are less promising lines of research into the treatment of aging are focused on manipulation of cellular metabolism. These approaches, such as targeting the mTOR pathway, largely derive from the study of calorie restriction and the cellular response to stress that is brought on by lack of nutrients. Calorie restriction extends average and maximum life span considerably in short-lived species, up to 40% in mice, for example. It increases the efficiency of cellular maintenance processes and makes cells more frugal in other ways. The impact of aging is slowed, as molecular damage accumulates less rapidly. Yet in long-lived species such as our own, short-term benefits are evident, but the practice of calorie restriction doesn't change human life span by a large amount.

It is thought by some in the research community that many of the changes that take place in short-lived mammals in response to nutrient stress have already evolved to operate consistently in long-lived mammals such as ourselves, precisely in order to make us long-lived. Calorie restriction produces such sweeping changes in the operation of cellular metabolism that researchers make only slow progress towards picking out the areas of importance, or towards expanding the catalog of interactions between pathways and mechanisms and aging.

Cellular metabolism becomes more dysfunctional with age in ways that can be assessed. As today's open access paper notes, some of these changes appear to cause further dysfunction in the immune system. Thus attempting to compensate for age-related metabolic issues by intervening in the mTOR pathway can improve immune function in old people to some degree, and it is believed that similar results can be obtained via other metabolic adjustment. It is worth noting that this is also true of exercise or the practice of calorie restriction! How and why does this improvement in immune function happen? The connections are complicated and still comparatively poorly explored.

Moving away from manipulation of metabolism towards the more direct approach of damage repair, one can improve metabolism by removing lingering senescent cells, a form of tissue damage. The presence of senescent cells disrupts cellular metabolism via the senescence-associated secretory phenotype, signaling that changes surrounding cell behavior for the worse. Removing damage that causes detrimental metabolic change seems a more promising approach than adjusting factors inside cells to try to minimize their response to that damage. Indeed, senescent cell clearance compares very favorably to mTOR inhibition in animal studies.

Targeting Aging: Lessons Learned From Immunometabolism and Cellular Senescence

Two hallmarks of aging, mitochondrial dysfunction and dysregulated nutrient sensing, are tightly associated with metabolic alterations. Increasing research is investigating the role of metabolism in controlling longevity. Three metabolic and nutrient sensing pathways, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuins, are under investigation as potential targets for aging.

Although all systems are affected, the hallmarks of aging substantially impact the immune system. It is well known that aging leads to progressive declines in innate and adaptive immunity. This immunosenescence is accompanied by chronic low-grade inflammation, or inflammaging. This results in increased susceptibility to infections, reduced response to vaccination, and increased prevalence of cancers, autoimmune and chronic diseases. Not surprisingly, given that deregulated nutrient sensing and mitochondrial dysfunction are hallmarks of aging, markers of inflammaging also coincide with markers of metabolic dysfunction.

Recent research has highlighted the importance of mitochondrial function and cellular metabolism in controlling immune cell function. Indeed, immunometabolism is critical for proper immune function. What remains to be fully explored is how age and age-associated factors, such as senescent cell accumulation, impact immunometabolism and therefore immune function. This research gap represents a potentially fruitful target for immune modulation in older adults.

Interventions that target dysregulated metabolism or senescence may prove fruitful for improving aged immune responses, leading to additional protection when dealing with infection. In fact, it has been demonstrated that low dose TORC1 inhibition in older adults decreased risk of all infections, upregulated antiviral immunity, and improved influenza vaccination responses. Although further research is necessary to fully elucidate the mechanisms by which metabolic changes with aging contribute to T cell dysfunction, current metabolic therapeutics may prove beneficial for targeting the aging immune system.

Furthermore, targeting senescent cells may also improve immunometabolism with aging. Senolytics, drugs that target senescent cells, have shown great promise with treating age-related diseases and phenotypes. With age, there is increased insulin resistance driven by dysfunction in adipose tissue. Senescent adipocyte progenitor cells were found to be the root cause of dysfunction and when cleared with senolytic treatment, insulin resistance is reversed. Interestingly, many immune cells (including T cells, B cells, and NKT cells), are thought to exacerbate insulin resistance. Taken together, the ablation of the senescence-associated secretory phenotype using senolytics could possibly reverse the deleterious activity of these immune cells which could be beneficial beyond insulin resistance. Furthermore, senolytics may reduce CD38 expressing macrophages and preserve NAD+ levels with aging, offering a promising strategy to enhance metabolic fitness with age.

Researchers here move from rodents to sheep in testing the ability of a comparatively simple autologous cell therapy to improve regeneration following tendon injury. The results appear much the same in both species, which suggests that human trials will produce positive results. This approach will join a few other cell therapies aimed at tendon repair and tested in human trials over the past twenty years. The field moves slowly, like much of medicine.

In the search for new and better ways to heal injured tendons, the medical world is looking closely at regenerative therapies. In particular, autologous adipose micrografts (AAMGs) and stromal vascular fraction (SVF) are showing promise. SVF, derived from adipose tissue, contains heterogeneous cell populations including stem cells and immune cells involved in regeneration. In a previous study on rats, AAMGs and SVF improved tendon healing in 60 percent to 70 percent of treated animals. The purpose of a new study was to evaluate the effects of AAMG in sheep with tendinopathy, as larger animals are more comparable to humans than are rodents.

This is also the first study on an animal model employing a mechanical fat breakdown system as an alternative to enzymatic digestion to isolate the SVF. This procedure is able to maintain the microenvironment of the perivascular niche, while at the same time removing any pro-inflammatory factors. The residual SVF contain pericytes that are able to gradually convert into activated adipose stem cells.

The team carried out the study by inducing tendinopathy in both common calcaneal tendons (CCT) of 16 female sheep. Tendinopathy is a breakdown of collagen in a tendon, resulting in burning pain, reduced flexibility and limited range of motion. Four animals were assigned to a non-treated group as a control. Each of the other 12 sheep had one CCT injected with AAMG, while its contralateral CCT was left untreated. At 8 weeks after treatment, the treated group showed a final tendon diameter (9.1 ± 1.4 mm) and a hardness expression (62%) that were similar to the original healthy tendon (8.1 ± 1.1 mm; 100%), with a significant recovery compared with the control group (9.5 ± 1.7 mm; 39%). Moreover, histological analysis of the treated group revealed an improvement in the fiber orientation score, fiber edema score, infiltrative-inflammatory process, and necrosis score compared with control group.

Link: https://www.eurekalert.org/news-releases/925276

The age-related decline of the immune system is complex. There are many facets to the issues of increased systemic inflammation and reduced immune competence. Here, researchers show that a necessary population of memory B cells is reduced with age, and this impairs the ability of the immune system to respond to novel threats. Clearing the entire B cell complement has been attempted in mice, and shown to improve function. B cells regenerate rapidly following clearance, even in old animals. It is as yet unknown as to how that approach interacts with the dysfunction described here, but B cell clearance does address the problem of an accumulation of dysfunctional age-associated B cells.

Immunological memory is the ability of our immune system to remember previously encountered pathogens. Infections are rare in adults thanks to their large repertoire of specific memory T cells and memory B cells generated by previous antigenic experiences. In the elderly, susceptibility to infections increases again. We focused our attention on B cells that change with age in number and type. As a result of infection or vaccination, B cells become memory B cells (MBCs) and plasmablasts (PBs) able to produce high affinity antigen-specific antibodies. MBCs can be identified by the expression of the CD27 marker. The intensity of expression of CD27 defines two populations, CD27dull and CD27bright MBCs.

We show that the elderly have a significant reduction of CD27dull memory B cells, a population that bridges innate and adaptive immune functions. CD27bright MBCs are generated exclusively by a T cell-dependent mechanism and under a strong selective pressure by an antigen. Compared to children, elderly individuals have more CD27bright MBCs. Taken together, this suggests that their immune system may be equipped to react against well-known antigens but has a reduced ability to respond to new pathogens. Moreover, after in vitro stimulation, B cells from older individuals produced significantly fewer antibodies compared to younger individuals.

Link: https://doi.org/10.3389/fimmu.2021.690534

A growing school of thought sees persistent viral infection as an important contributing factor in age-related neurodegeneration. The widely varying burden of infection that is present in the population could help to explain the puzzling epidemiology of conditions such as Alzheimer's disease, in that only some of the people with evident risk factors in fact go on to develop dementia. A simplistic view of the role of viral infection, particularly by persistent herpesviruses, is that it produces chronic inflammation in brain tissue, and that inflammation contributes to the many forms of molecular pathology observed in neurodegenerative conditions.

The immune system of the brain is distinct from that of the rest of the body, the two sides separated by the blood-brain barrier surrounding blood vessels in the central nervous system. In recent years, increasing attention has been given to the age-related dysfunction of innate immune cells in the brain, the microglia, and the contribution of that dysfunction to neurodegeneration. Microglia in older individuals are more inflammatory in general, and some become senescent, producing an outsized amount of pro-inflammatory signals. Studies in mice have shown that using senolytic drugs to clear senescent cells, including senescent microglia, from the brain can reverse neuroinflammation and pathology characteristic of neurodegenerative conditions. The interesting question is to what degree this inflammatory microglial dysfunction is the consequence of persistent infection in the population as a whole.

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

The physiological function of resting, non-activated microglia in brain homeostasis is not well understood. Activated microglia may acquire paradoxical, opposite functions, either supporting regeneration and repair, or driving neuroinflammation. The triggers and mechanisms driving the cells towards one or the opposite functional direction are not well understood. However, inflammatory microglia can be harmful and destructive to the brain, whereas regenerative microglia may interfere with physiological brain remodeling processes.

Microglia are essential to the healthy brain, as they contribute to many brain functions and help sustain the physiological brain structure. Belonging to the innate immune system of the brain, microglia contribute to an immune response against any brain-invading agent, as well as following traumatic and neurovascular brain damage. They help with resolving tissue damage and support regeneration and restauration of structure and function. However, microglia may get out of control and out of balance resulting in augmenting brain damage or sustaining chronic pathologies like neuroinflammation and inducing or enhancing neurodegeneration. In such case, microglia may enhance brain aging.

The more we age, the more our immune system gets toward a more inflammatory status. The increased systemic inflammatory immune status also affects microglia, resulting in decreased physiological neuroregeneration and remodeling. The inflammatory status is certainly enhanced and accelerated through frequent or chronic viral infections. The increased and chronic inflammatory status in the brain may contribute to neurodegeneration due to increased neuronal cell death and reduced neurogenesis, reduced remodeling and irreparable damage to the neuronal network, resulting in an enhanced or accelerated brain aging process.

In the context of microglia and viral infection, most research has been done in HIV, where the association has been shown for neurocognitive decline. However, there is little information available about the cellular and molecular mechanisms that contribute to or influence the chronic HIV infection and corresponding involvement of microglia, which requires more future research. The same accounts for other viruses, including flaviviruses, human herpes viruses, and SARS-CoV-2.

Many lines of evidence point to kidney function as being particularly important to the health of organs throughout the body. To pick one example, one of the better known longevity-associated genes, klotho, appears to act in the kidney, and yet is well known for producing improvements in cognitive function. Here, researchers discuss much of the other evidence related to the accelerated aging observed in chronic kidney disease patients. Once the kidney starts to decline, near everything else in the body follows, with cardiovascular issues being a particularly prominent part of the problem.

The characteristics of chronic kidney disease (CKD) are similar to those of the aging process; therefore, it has been hypothesized that CKD promotes premature aging associated with related diseases. Furthermore, chronic diseases usually observed in aging, such as cardiovascular disease (CVD), inflammation, vascular calcification, mineral, and bone disorders, and chronodisruption (chronic alteration of circadian rhythms), are markedly frequent in patients with CKD.

CVD is the most clinically relevant comorbidity associated with CKD. The coexistence of both diseases could be explained by the following: (1) patients with CKD have a higher prevalence of non-traditional cardiovascular risk factors, (2) many cardiovascular risk factors exacerbate CKD progression, and (3) CKD itself can be considered a risk factor for CVD. According to 2013 data from the U.S. Renal Data System, an estimated 43% and 15% of patients with CKD experience heart failure and acute myocardial infarction in their lifetime (versus healthy persons: 18.5% and 6.4%, respectively).

The development of CVD in patients with CKD is due primarily to endothelial dysfunction. Endothelial cells in patients with renal disorders experience premature senescence due to received stress signals, which may lead to apoptosis. Under physiological conditions, endothelial cells have a non-adherent and anticoagulant surface; however, molecules expressed on the surface of damaged endothelial cells may be altered, increasing cell adhesion capacity. Platelets bind to the damaged surface, triggering the onset of coagulation with consequent inflammation and thrombosis, thereby causing cardiovascular accidents.

Several factors, such as inflammation, oxidative stress, primary diseases such as hypertension or diabetes, and hyperlipidemia, contribute to endothelial deterioration in CKD. Another example is hyperphosphatemia, which is present in many patients with renal disorders. High phosphate concentrations increase oxidative stress and reduce the concentration of nitric oxide, which the endothelial cells release to relax and avoid the rigidity of the arteries and regulate endothelial permeability.

Link: https://doi.org/10.3390/ijerph18158044

The research noted here is one of many different views into the decline in cell and tissue activity that takes place in old age. One can look at the way in which cancer rates decline with age after peaking in the 60s and 70s, for example. Or the phenomenon of diminished protein synthesis in old tissues. Or reduced calorie intake in older people. Many of the manifestations of age are reactions to underlying causes. A general slowdown in cell activity has the look of something that depends upon environment, given the various studies showing that many types of cell taken from old individuals can still perform to youthful levels if given a youthful environment.

To come up with a number for total daily energy expenditure, researchers relied on the "doubly labeled water" method. It's a urine test that involves having a person drink water in which the hydrogen and oxygen in the water molecules have been replaced with naturally occurring "heavy" forms, and then measuring how quickly they're flushed out. Scientists have used the technique to measure energy expenditure in humans since the 1980s, but studies have been limited in size and scope due to cost. So multiple labs decided to share their data and gather their measurements in a single database, to see if they could tease out truths that weren't revealed or were only hinted at in previous work.

Energy needs shoot up during the first 12 months of life, such that by their first birthday, a one-year-old burns calories 50% faster for their body size than an adult. "Something is happening inside a baby's cells to make them more active, and we don't know what those processes are yet." After this initial surge in infancy, the data show that metabolism slows by about 3% each year until we reach our 20s, when it levels off into a new normal.

Midlife was another surprise. Perhaps you've been told that it's all downhill after 30 when it comes to your weight. But while several factors could explain the thickening waistlines that often emerge during our prime working years, the findings suggest that a changing metabolism isn't one of them. In fact, the researchers discovered that energy expenditures during these middle decades - our 20s, 30s, 40s and 50s - were the most stable.

The data suggest that our metabolisms don't really start to decline again until after age 60. The slowdown is gradual, only 0.7% a year. But a person in their 90s needs 26% fewer calories each day than someone in midlife. Lost muscle mass as we get older may be partly to blame, since muscle burns more calories than fat. But it's not the whole picture. "We controlled for muscle mass. It's because their cells are slowing down."

Link: https://www.eurekalert.org/news-releases/924765

The immune system has many roles. It doesn't just destroy invading pathogens, but also hunts and kills potentially harmful cells, such as those that have become senescent or potentially cancerous. Further, immune cells are intricately involved in the processes of tissue maintenance. Regeneration from injury is a complicated dance of signals and changed states carried out between stem cells, immune cells, and somatic cells. In the central nervous system, immune cells take on additional responsibilities related to maintaining and changing synaptic connections between neurons.

The immune system fails with age. Its failure is complex, built of many separate, interacting failures that take place in both the biological systems responsible for manufacturing immune cells, and in the many distinct and varied populations that make up the immune system as a whole. The result is an immune system that is both chronically overactive, producing constant inflammation that disrupts normal tissue maintenance and function throughout the body, but also incapable of effectively destroying pathogens and cancerous or senescent cells.

It is precisely because the immune system is involved in so much of the correct function of the body and mind that it is an important target for the development of rejuvenation therapies. A considerable fraction of the dysfunction, frailty, suffering, and mortality of age is driven by the failure of the immune system, its decline into chronic inflammation. If the immune system of every 60-year old could be restored to that of a 40-year old, incidence of age-related disease and mortality could be expected to become significantly lower.

There are many potential approaches to restoring function to the aged immune system, a range of which are discussed by the authors of today's open access paper. For example: replacing the hematopoietic stem cell population responsible for creating immune cells; regenerating the involuted thymus, where T cells mature; selective destruction of problematic immune cell population that grow with age, such as senescent T cells or age-associated B cells; and so forth. The next few decades could well be a very inventive time in the treatment of immune system aging, given sufficient investment in the right lines of research and development.

Targeting immune dysfunction in aging

Aging is a multifactorial phenomenon that affects virtually all cells and organ systems in the human body resulting in a progressive functional impairment and loss of homeostasis. One of the most dysregulated systems in aging is the immune system, with alterations in several biological and physiological processes that have significant repercussions on the overall well-being of the organism. The main roles of the immune system include the defense of the host against pathogens, the maintenance of homeostasis with clearance of dead cells and the regulation of healing processes. These activities are performed by specialized cells, that can activate general immune responses (innate immunity) or build specialized long-lasting defense against specific antigens (adaptive immunity). The progressive deterioration of the immune system affects both of these systems in elderly individuals, increasing susceptibility to infections, cancer, and inflammatory diseases, while delaying wound healing processes and reducing the ability to build an antibody response to some types of vaccination.

Indeed, the incidence of several infectious diseases, both bacterial and viral, increases with age and can be modeled based on immune system decline. In the same computational study, the authors showed that this is also true for cancer, indicating that the alteration of the immune system in aging may contribute to increased cancer incidence in the elderly. This work expands the scientific evidence on the relation between aging, immunity and cancer, but the exact ways in which they affect and influence each other remains debatable. Also autoimmune diseases have been investigated in the context of aging, with some evidence suggesting that they tend to be less frequent and less severe in elderly individuals, consistent with an overall decline in immune cell activity.

The dysfunctional immune system in aging has been associated with two processes defined as "immunosenescence" and "inflammaging". Immunosenescence, first proposed more than 40 years ago, is defined by the gradual deterioration of the immune system, which loses its ability to respond to infections and build effective long-lasting immune memory. More recently, studies have highlighted how several cell types of the innate and adaptive immune system undergo phenotypic changes during aging that impair their basic functions. At the beginning of 2000, a second phenomenon that affects the immune system in aging was proposed, termed inflammaging. While inflammatory processes are essential for the defense against foreign pathogens and clearance of dead and aberrant cells, their dysregulation and overactivation in the elderly causes a chronic inflammatory state that persists and promotes the development of inflammatory diseases associated with aging. These two processes are deeply interconnected, and can influence and maintain each other to create an imbalanced immune environment that is not only dysfunctional, but even acts as a driver for diseases development.

Individual differences are now starting to delineate a personalized way of aging that adds complexity to the investigation of deregulated processes. In this view, the identification of different immune ageotypes will help define subpopulations of elderly individuals with characteristic immune signatures and their longitudinal monitoring might help develop potential personalized anti-aging treatments. In this review, we report and discuss the contributions of different immune cells in aging and address the latest therapeutic options that have been proposed with the overall goal to rejuvenate or at least revitalize the immune system and slow down or even reverse immune aging.

It is interesting to see the sizable degree to which sufficient physical activity can mitigate many of the effects of aging in muscle tissue. It is well known that exercise programs improve muscle function and reduce mortality in later life. In the study reported here, the intent was to distinguish (a) effects of aging from (b) effects of lack of exercise in later life on mitochondrial function in muscle tissue. Older people in wealthier parts of the world largely live a sedentary life. Few exercise to the degree that they should in order to maintain function and health. Researchers here find that reduced mitochondrial function in muscle in their study population is largely the result of insufficient exercise. They also note that an adequate level of exercise to maintain mitochondrial function in youth ceases to be adequate in later life, only reinforcing the importance of physical activity to health in old age.

One of the distinctive features of aging is the progressive loss of muscle mass and physical function, collectively known as sarcopenia. In parallel with the progressive loss of muscle function, mitochondrial respiratory activity in human skeletal muscle has been shown to decrease with advancing age in healthy men and women. Furthermore, protein levels of the mitochondrial master regulator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) were found to correlate with walking speed in healthy older adults. Some preclinical studies indeed suggest that the reduction in muscle mitochondrial function may underlie the decline in muscle health during aging. Therefore, it is tempting to speculate that augmenting mitochondrial function could be a potential strategy to counteract aging-associated decline in physical function.

Although some human studies have addressed age-related alterations in muscle mitochondrial function in relation to the decline in skeletal muscle function, the available data in humans is scarce and the few available studies often focus on either the decline in muscle function or concentrate primarily on the mitochondrial alterations. Additionally, the age-associated decline in mitochondrial function is not completely attributable to aging per se and may also be explained, in part, by an age-related decline in physical activity (PA). Decreased PA can adversely affect mitochondrial capacity.

To delineate these relationships, we conducted a cross-sectional study with detailed phenotyping in groups of young versus older human participants, with a range in oxidative capacity and physical function. The first aim of the study was to assess if mitochondrial function is reduced in older compared to young participants with a similar level of habitual PA, and to examine how mitochondrial function relates to muscle function.

Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle.

Link: https://doi.org/10.1038/s41467-021-24956-2

One of the more interesting discoveries of the past few decades in cancer research has been the identity of surface markers such as CD47 that normally act to protect important cells from being attacked and destroyed by immune cells - a "don't eat me" signal. Cancers abuse such mechanisms in a variety of ways, both directly, in cancerous cells, and indirectly, via subversion of regulatory immune cells that are protected by such surface markers, in order to suppress the immune response to the cancer. Targeting CD47 has proven a promising approach to the treatment of cancer, but it has side-effects. There are always necessary cells in the body that should be protected in this way, but that become casualties as a result of treatment.

For decades, researchers have known that the immune system not only plays a key role in battling cancers through the direct action of killer T cells and other components, but also opposes these efforts through cells known as regulatory T cells (Tregs). These Tregs help to regulate the immune response by preventing various immune cells from becoming overactive and causing autoimmune diseases. However, they also accumulate in tumors, shielding them from immune attack.

Tregs maintain a balance of two proteins on their surfaces - CTLA-4 and CD47 - that respectively broadcast "eat me" and "don't eat me" signals to phagocytes that keep Tregs in check. Various immunotherapies have sought to boost the "eat me" signal or decrease the "don't eat me signal" to reduce Tregs in tumors. However, each strategy has drawbacks: Increasing the "eat me" signal has systemic effects that spur autoimmunity, while decreasing the "don't eat me" signal has only shown promise for treating blood cancers, such as leukemias.

Searching for a new way to deplete Tregs, researchers created a two-arm molecule that simultaneously increases the "eat me" signal while blocking the "don't eat me" signal to prompt phagocytes to consume those immune suppressive cells. When it was injected into mouse models of colon cancer, they found that it preferentially depleted Tregs in tumors without affecting those in the rest of the body, sparing the animals from treatment-induced autoimmune disease. However, dosing these animals with equivalent, separate amounts of the "eat me" booster and "don't eat me" blocker had systemic autoimmune side effects, suggesting that combining them within one molecule is key to reaching Tregs in tumors. As the number of Tregs decreased with treatment, the animals' tumors shrank significantly. This strategy also worked in mice carrying human lung cancer tumors, suggesting that it could be viable in human patients.

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2021/cancer-protectors.html

The gut microbiome shifts with age, reducing beneficial populations and increasing harmful populations that contribute to chronic inflammation. Today's research materials can be added to other examples in which an intervention to restore a more youthful gut microbiome in old animals results in improved function, both through a reduction in inflammation and increased production of beneficial metabolites such as butyrate, that promotes increased levels of BDNF and neurogenesis, among other effects. It is a challenge to pick apart which of the mechanisms are most influential, but restoring a more youthful gut microbiome is clearly beneficial.

Fecal microbiota transplantation from young to old is an approach to the treatment of aspects of aging that could be comparatively rapidly rolled out in human medicine, in principle at least, given that such transplants are already used for cases in which the gut is overtaken by pathological bacteria. It isn't the only potential treatment with evidence to support its benefits. Innoculation with flagellin provokes the immune system into better gardening the gut microbiome, removing more of the pathological species, and also has some safety data in human patients already as a result of use as a vaccine adjuvant. More speculatively, it should be possible to achieve similar results via high dose probiotics, though here there is a lot more work to do with regard to establishing the right mix, dose, approach to delivery. It is entirely plausible that none of the products presently available in the marketplace can be combined to achieve the desired result.

Fecal transplants reverse signs of brain aging in mice

To test whether a young microbiome could reverse signs of aging, researchers took fecal samples from 3- to 4-month-old mice, the equivalent of young adults, and transplanted them into 20-month-old animals - ancient by mouse standards. The scientists fed a slurry of feces to the old mice using a feeding tube twice a week for 8 weeks. As controls, old mice received transplants from fellow old mice, and young from young. The first thing the team noticed was that the gut microbiomes of the old mice given young mouse microbes began to resemble those of the younger ones. The common gut microbe Enterococcus became much more abundant in old mice, just as it is in young mice, for example.

There were changes in the brain as well. The hippocampus of old mice - a region of the brain associated with learning and memory - became more physically and chemically similar to the hippocampus of young mice. The old mice that received young mouse poop also learned to solve mazes faster and were better at remembering the maze layout on subsequent attempt. None of these effects was seen in old mice given old mouse feces.

Microbiota from young mice counteracts selective age-associated behavioral deficits

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.

It is becoming clear that transthyretin amyloid accumulation makes a meaningful contribution to cardiovascular disease and a range of other conditions over the course of normal aging. It remains poorly explored, but that will likely change in the years ahead now that there are treatments capable of reducing the amount of transthyretin amyloid in the body. Clinical development of these therapies is initially focused on the rare cases of transthyretin amyloidosis in which inherited mutations greatly speed the process of amyloid formation, but some of them appear to also work for the amyloids that form in normally aged individuals. The ability to remove transthyretin amyloid in humans is all still quite new as of recent years, however, and progress is always very slow in the research and medical communities.

The native tetrameric form of transthryetin (TTR) is a protective factor against oxidative stress. TTR is involved in reactive oxygen species (ROS) balance, extracellular matrix (ECM) remodeling, autophagy, apoptosis, reverse HDL cholesterol transport, proliferation, and angiogenesis under physiological conditions and in pathological disorders or stress-induced insults. The formation of TTR amyloid is induced by oxidative modification, aging, mutation, metal ions (including Ca2+), plasmin, and negatively charged polymers. The factors that compromise structural stability and lead to amyloid formation upon dysregulation may be responsible for improper/mislocated induction of TTR and result in cytotoxic TTR amyloid.

The contribution of TTR to cardiovascular and osteoarticular diseases is associated with the formation of TTR amyloid and calcification in the vascular and ligament tissues. Low levels of TTR in the plasma are observed in CVDs and the majority of osteoarticular disorders. It is difficult to determine whether changes in the processes or TTR levels correspond to a cause or a consequence of amyloid formation and whether adverse effects observed in amyloid-induced diseases are a consequence of amyloid overload or a loss of the protective functions of TTR.

Unaggregated/native and aggregated/amyloid TTR forms are interconnected in the following loops. Vicious cycle 1, oxidative stress: oxidative modifications lead to TTR destabilization and pathological amyloid, which increases oxidative stress. Properly folded TTR is a factor that suppresses oxidative stress, inhibits intracellular Ca2+ influx, ROS production, membrane permeabilization, apoptosis, and autophagy, and promotes the assembly of oligomeric proteins into larger, less toxic aggregates. Vicious cycle 2, Ca2+: TTR amyloid is formed in situ in response to high Ca2+ concentration, which, in turn, promotes TTR destabilization and amyloid deposition, which entraps more Ca2+. Vicious cycle 3, inflammation: plasmin or other factors induce the formation of TTR amyloid. Amyloid deposits cause plasmin activation and induce inflammation, which, in turn, promotes amyloid formation. Vicious cycle 4, lipids: cholesterol and anionic phospholipids bind TTR and promote TTR aggregation. On the other hand, aggregated TTR alters membrane fluidity and induces cytotoxic effects, upregulating TTR aggregation.

Link: https://doi.org/10.3390/cells10071768

IGF-1 is one of the better studied areas of metabolism relevant to determining the pace of aging in a species, involved in the regulation of tradeoffs between growth and sustained function. In the context of the evolution of aging, a mechanism exhibiting antagonistic pleiotropy is beneficial in youth but harmful in later life. Natural selection acts more strongly on features of a youthful individual, favoring those more capable of reproducing prior to mortality via predation and disease. Features are selected on the basis of early life success with litter regard for whether or not they are sustainable. Thus we wind up with a world in which near all species have a biochemistry that is set up for a fast start to life, and then runs awry and degenerates with the passage of time.

While insulin-like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF-1 levels and clinical disease. We examined prospective associations of serum IGF-1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns.

First, IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF-1 are protected from disease, while older individuals with high IGF-1 are at increased risk for incident disease or death. Second, the association between IGF-1 and risk is generally U-shaped, indicating that both high and low levels of IGF-1 may be detrimental.

With the exception of a more uniformly positive relationship between IGF-1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age-associated diseases. These data suggest that IGF-1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.

Link: https://doi.org/10.1111/acel.13443

Neuromuscular junctions link the nervous system with muscle tissue, allowing control of muscle activity. Muscle mass and strength decreases with age, condition known as sarcopenia. This is a process that can be turned back to some degree by strength training, even in late life, but ultimately leads to frailty. Muscle isn't just a mechanical tissue, it also has important metabolic roles relevant to the regulation of immune system activity, inflammation, and more.

There are many viewpoints on which of the mechanisms of sarcopenia are likely the most important, the best targets for intervention. For example, leucine processing is less effective in aged tissues, and supplementation with leucine is an easy intervention to test. The results in human trials are largely positive, but certainly not spectacular. Stem cell function and chronic inflammation are thought to be important, but reliable and broadly available approaches to address these issues are somewhat lacking.

A sizable contingent in the research community sees sarcopenia as primarily a neuromuscular issue. The neuromuscular junctions become damaged and dysfunctional, and the consequent lack of signaling into muscle tissue leads to declining muscle tissue maintenance and function. As is usually the case for age-related conditions, coming to a definitive answer on the importance of this mechanism, relative to all of the others, would require a way to repair and restore neuromuscular junctions to a youthful level of function without affecting other aspects of aging. Here also, viable approaches are presently lacking.

The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease

Adult skeletal muscles decline in size with age, resulting in a loss of muscle mass (sarcopenia) and consequent weakness. The impact of muscle loss is exacerbated by the corresponding decline in the quality of the preserved muscle (e.g., amount of force per unit volume). These deficits, together with increased susceptibility to injury, reduced recovery, and proprioceptive decline, predispose the risk of falls and related injuries, which are linked to morbidity and mortality. Sarcopenia has enormous social and economic benefits: a 10% reduction in prevalence alone would result in savings of well over a billion dollars. Despite significant advances in understanding the molecular alterations in aging, the pathophysiology of age-associated muscle weakness remains unclear.

Some describe sarcopenia as a primary muscular pathology, with only minimal changes in the peripheral nerves and motor units occurring much later than the onset of sarcopenia. Indeed, aging muscles share several similarities to muscle dystrophies. Synaptic nuclei in aged muscle have abnormal expression of nuclear proteins, such as reduced LMNA gene expression, suggesting that muscle dysfunction with aging may be similar to that seen in laminopathies. Other similarities between aging muscle and dystrophic muscle include a loss of dystrophin with age. However, there is no consensus on other components of the dystrophin glycoprotein complex (DGC), with reports of increased, decreased and unchanged expression of DGC components.

However, the diminished muscle quality suggests additional neural contributions of to muscle wasting. A number of age-associated pathological changes have been reported in peripheral nerves and neuromuscular junctions (NMJs), which have even been posited to initiate and drive the muscle pathology in sarcopenia. There are strong correlations between aging and deficits in axonal transport in peripheral neurons. These deficits impair the delivery of vital synaptic and energetic cargoes to the pre-synaptic terminal and occur concurrent with age-associated changes in the neuronal cytoskeleton. Neurofilaments, the primary structural components of motor neurons and a key regulator of axonal caliber and cytoskeletal transport, appear particularly susceptible to age, based on observed changes in their density, organization, and phosphorylation state in aged mice.

Just as the NMJ dictates muscle physiology, it also influences muscle pathology. Several lines of evidence suggest that age-related changes in the NMJ play a key role in musculoskeletal impairment with aging. Indeed there is increasing consensus that functional muscle denervation is a principal factor leading to sarcopenia, and some even describe sarcopenia primarily as a "disorder of the NMJ". Despite the continuing ambiguity of sarcopenia etiology, it is clear that, at a minimum, age-dependent changes in the peripheral nerve and NMJ contribute to the muscle pathology in sarcopenia.

Many of the approaches to selective cell destruction pioneered in the cancer research community distinguish target cells from bystander cells via cell surface markers. Do senescent cells have a sufficiently distinct set of surface markers to safely employ this strategy to reduce the burden of cellular senescence in old tissue, and thereby produce rejuvenation of tissue function? Almost certainly yes, as the immune system uses exactly this approach to identify and kill senescent cells. Identifying the surface markers involved is a plausible goal, presently underway. Several biotech companies work on forms of senolytic immunotherapy, based on the present state of knowledge regarding senescent cell surface features. The open access paper noted here discusses this topic in more depth.

Cellular senescence is a phenotype associated with limited replicative capacity and irreversible growth arrest of primary cells first described in the early 1960s. Senescent cells are characterized by specific phenotypical features including enlarged and flattened cell morphology, enhanced lysosomal beta-galactosidase activity, increased expression of cell cycle inhibitors (p21Cip1/Waf1, p16Ink4A, p15Ink4B, and p53), and high metabolic activity including GSK3, AMPK, and mTOR pathways. In this regard, senescent cells differ from quiescent cells, which instead display a reversible cell cycle arrest and are characterized by a low metabolic status, a decrease in glucose uptake, and a reduction in mRNA translation.

Senescent cells arise in culture and in tissues following a variety of damaging insults such as DNA damage, oxidative stress, telomere shortening, mitochondrial dysfunction, and aberrant activation of oncoproteins. Besides the role of damaging agents, cellular senescence may also be induced by physiological stimuli including developmental and repair signals. Therefore, transiently-induced senescence plays a beneficial role in physiological events such as organogenesis, tissue homeostasis, and wound repair. Furthermore, the upregulation of cell cycle inhibitors in senescent cells plays a crucial role in their ability to suppress the development of cancer, thus senescence is considered as a tumor-suppressor phenotype.

Alongside the beneficial roles associated with transiently-induced senescence, the accumulation of senescent cells exerts detrimental effects on the functionality of tissues and organs. Indeed, the active metabolism of senescent cells drives the production of several members of cytokines, chemokines, growth factors, and proteases collectively known as senescence-associated-secretory-phenotype (SASP). Members of SASP include pro-inflammatory cytokines and chemokines such as IL-6, IL-8, and matrix degrading enzymes like MMP-1, MMP-3, and MMP-10. The release of such molecules in the cellular microenvironment induces a pro-inflammatory milieu, therefore leading to immune cell recruitment with the reinforcement of inflammation, paracrine senescence, tissue remodeling, and tissue degeneration.

Cellular senescence is one of the processes contributing to aging. With aging, senescent cells accumulate in the body tissues and associate with age-related pathologies, which include, among others, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), atherosclerosis, type 2 diabetes, tissue fibrosis, and cancer. Given the role of senescence in aging and age-associated diseases, there is a growing interest in developing approaches in order to target senescent cells. Much of this effort is focused on the development of strategies aimed at the clearance of senescent cells in vivo to reduce their accumulation and the subsequent alterations in tissue functionality. Here, we review the main approaches used to identify senescent cells in vitro and in vivo, with a focus on novel biomarkers of cellular senescence localized on the cell surface. We discuss the roles of surface proteins in SASP production and in the regulation of immune surveillance. Finally, we highlight the main therapeutic approaches that can be adopted to eliminate senescent cells in vivo by pharmacological and genetic approaches, with a focus on targeting the senescent surfaceome.

Link: https://doi.org/10.3390/cells10071740

Researchers here note that undertaking strength training and aerobic exercise acts to reduce mortality due to cancer, to a similar degree as these activities are known to reduce all cause mortality in later life. The mechanisms involved are likely diverse, but it is worth noting that (a) muscle tissue is metabolically active in beneficial ways, such that more muscle is better than less muscle, (b) better immune function is linked to exercise, and immune surveillance is critical to cancer prevention, and (c) exercise helps to reduce chronic inflammation, where chronic inflammation helps to drive the establishment and development of tumors.

Regular muscle strengthening exercises associated with aerobic activities can reduce cancer mortality, according to a systematic review of epidemiological studies. Workouts with squats, rowing, planks, weight training and so on can reduce the probability of dying from cancer by 14%. When these exercises are combined with aerobic activities, the benefit is even greater, potentially reducing mortality by 28%.

Epidemiological research using demographic data has shown that physical activity in general reduces the risk of breast, endometrial, stomach, throat, kidney, and bladder cancer. The present study found that muscle strengthening exercises can reduce the risk of kidney cancer by 26%. Statistically significant correlations were not found between muscle strengthening exercises and tumors primarily located in the colon, prostate, lung, pancreas, bladder, esophagus, and rectum, as well as melanoma, multiple myeloma, lymphoma, leukemia and cancers of the digestive system, owing to the limited number of studies.

The study also corroborated the recommendations of the World Health Organization (WHO) regarding regular aerobic exercise for adults: 150-300 minutes per week if moderately intense, 75-150 minutes of vigorous exercise, or an equivalent combination. The WHO also recommends twice-weekly strengthening exercises. The researchers analyzed 12 studies involving 11 cohorts and a control case, with participation by a total of 1,297,620 people, who were monitored in studies lasting between six and 25 years. The analysis suggested that strength training twice a week can protect against cancer.

Link: https://agencia.fapesp.br/combination-of-muscle-strengthening-and-aerobic-exercises-can-reduce-cancer-mortality/36480/

Is amyloid-β aggregation an important cause of Alzheimer's disease, or is it a side-effect of other, more important mechanisms? Near all age-related conditions are complex, with multiple interacting mechanisms involved. Absent a way to remove just one of those mechanisms, it is quite hard to say which are more or less important. In Alzheimer's disease this is made worse by the fact that the animal models are very artificial: few shorter lived mammals naturally develop anything even remotely resembling the biochemistry of Alzheimer's disease. Thus whether or not a treatment produces benefits in animal models is a poor indicator of whether or not it will produce benefits in humans. The quality of the model rests on unproven assumptions about the relevance of specific mechanisms to the condition.

There are now several approaches shown to be capable of removing a large fraction of amyloid-β from the brains of human patients, after many years of slow and painful development. The evidence from human trials shows that benefits to cognitive function and disease progression are muted at best, and more likely absent. This is unfortunate, but we can't expect every choice of target to be a success.

The poor outcomes of trials of anti-amyloid immunotherapies strongly suggest that amyloid-β is not an important mechanism in Alzheimer's disease, or at least if it is, then this is the case only during the early, slow development of the condition, setting the stage for immune dysfunction, neuroinflammation, and tau pathology. Because the onset of amyloid-β aggregation is so slow, it might be years yet before further trials of amyloid-β clearance reveal whether or not it produces benefits to patients in terms of postponing or preventing mild cognitive impairment and Alzheimer's disease. Nonetheless, this is how work on aging and age-related conditions must progress: the most optimal way forward is to find a plausible mechanism, address it, and see what happens. Then move on to the next.

On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away

The FDA's controversial approval of aducanumab hinged on the premise that clearance of amyloid would be "reasonably likely" to bestow a cognitive benefit. Data presented at the Alzheimer's Association International Conference (AAIC) support the idea that two other antibodies could clear that low bar, as well. Researchers reported that the plaque-dissolving strength of donanemab, an antibody trained against forms of amyloid-β (Aβ) detectable only in plaques, tracked closely with plummeting plasma p-tau217. Weaving their data into a disease-progression model that had been generated from past trial data, they claimed that the amyloid- and tau-lowering effects of the drug correlated with a slowing of cognitive decline. Separately, data from lecanemab's Phase 2 trial and open-label extension studies provided yet more support for that antibody's disease-modifying effect, despite the travails that have beset its path through clinical development.

Both donanemab and lecanemab have received breakthrough therapy status from the FDA. Similarly to aducanumab, this means that their sponsors could apply for accelerated approval based primarily on changes in surrogate biomarkers that demonstrate amyloid reduction.

The donanemab trial enrolled 257 participants who had early symptomatic AD, amyloid in their brains, and - notably - an intermediate level of neurofibrillary tangles based on PET scan. After an initial period, when 131 volunteers randomized to the treatment group gradually received higher and higher doses of donanemab, the trial settled in on monthly infusions of 1,400 mg donanemab. This was given until a person's amyloid burden dropped below 25 centiloids - the level in healthy young controls - at which point the dose was lowered to 700 mg. If amyloid fell below 11 centiloids, or below 25 for two consecutive scans, the person was switched to placebo.

The 76-week trial met its primary cognitive endpoint, showing a 32 percent slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS). By 24 weeks, donanemab had completely cleared plaques in 40 percent of participants in the treatment group; by the trial's end, 68 percent had reached normal levels. Once a person's amyloid complete cleared, their levels stayed down for the remainder of the trial. Among the participants with "deep amyloid clearance," i.e., amyloid levels below 11 centiloids, and who were switched to placebo by 24 weeks, amyloid burden crept up only slowly by 76 weeks, barely cresting 11 centiloids, on average. At this rate, it would take 14 years for amyloid to accumulate back to baseline level for this group, or about 90 centiloids.

There are no great surprises to be found in the research materials here, which report on the correlation between increasing frailty and mortality in later life. Those people who struggle the most with physical activities tend to be those most likely to die. It is interesting to compare this with research on smaller cohorts that demonstrates the ability of structured exercise programs to improve physical capabilities and reduce mortality in later life. While some fraction of frailty is connected to the deeper processes of aging, a sizable degree of the problem emerges as the result of a lack of physical activity in older people. The choice to live a sedentary lifestyle has consequences.

It is well known that motor function, also commonly known as physical function or physical capability, declines with age, but rates of decline differ widely from person to person. And while studies show that decline in cognitive (mental) skills can emerge up to 15 years before death, it's not clear whether the same is true for physical abilities. To explore this further, researchers examined several measures of motor function for their associations with mortality over a 10 year period from around age 65.

Their findings are based on over 6,000 participants of the Whitehall II Study, which recruited participants aged 35-55 years in 1985-88 to look at the impact of social, behavioural, and biological factors on long term health. Between 2007 and 2016, participants underwent motor function assessments on up to three occasions. These included measures of walking speed, chair rise time, and grip strength, along with self-reported measures of functioning and difficulties with activities of daily living, such as dressing, using the toilet, cooking and grocery shopping.

After taking account of other potentially influential factors, the researchers found that poorer motor function was associated with an increased mortality risk of 22% for walking speed, 15% for grip strength, and 14% for timed chair rises, while difficulties with activities of daily living were associated with a 30% increased risk. These associations became progressively stronger with later life assessments.

Link: https://www.eurekalert.org/news-releases/924274

The glymphatic system is a comparatively recently discovered feature of the brain, a drainage path for cerebrospinal fluid (CSF) that appears to become dysfunctional with age. That dysfunction may contribute to the progression of neurodegenerative conditions by allowing molecular waste, such as misfolded proteins, to build up in the brain. This is distinct from the age-related dysfunction of CSF drainage through the cribriform plate that may be a root cause of Alzheimer's disease, as that drainage is localized to the part of the brain in which Alzheimer's originates. Given that the glymphatic system is only recently characterized, many researchers interested in age-related conditions affecting the brain are still engaged in incorporating it into their view of risk, pathology, and potential treatments. Here, stroke and its aftermath, and potential connections to the glymphatic system, is the topic of interest.

Clearing the metabolic wastes and maintaining the fluid homeostasis are important for brain function. In most organs, the lymphatic network is responsible for the wastes clearance and fluid drainage. However, a hallmark of the brain is the absence of typical lymphatic structures. Due to the presence of blood-brain barrier (BBB), the movement of solutes and ions in the brain is strictly restricted. Cerebrospinal fluid (CSF) has been considered to be important for the exchange of water-soluble metabolites; however, its mechanisms remain largely unknown. In 2012 researchers reported the existence of the glymphatic system (GS) in the central nervous system (CNS), which is an alternative clearance system located in the perivascular space and aquaporin-4 (AQP4) dependent. Emerging evidence from human studies and rodent models suggests that the GS is crucial for maintaining brain health, and dysfunction of GS is closely associated with various neurological disorders, including aging, neurodegeneration, and acute brain injury. In parallel, the meningeal lymphatic vessels were discovered and demonstrated to participate in solutes transport and in immune surveillance.

Stroke, a major cause of death and disability, affects over 800,000 individuals annually. It has been well-recognized that the GS plays a crucial role in the pathophysiology of stroke, including brain edema, blood-brain barrier (BBB) disruption, immune cell infiltration, neuroinflammation, and neuronal apoptosis. Targeting the GS, therefore, has provided potential for the early risk assessment, diagnosis, prognosis, and therapeutic of stroke. In this review, we summarize the latest research progress in the GS, including the anatomy and function, the interaction with the meningeal lymphatic systems and the BBB, and the communication between astrocytes and other GS cellular components. We emphasize the role of the GS in pathophysiology of different stroke subtypes, especially the role of AQP4 in the pathophysiology of stroke.

Link: https://doi.org/10.3389/fnagi.2021.689098

It is fairly settled that evident particulate air pollution, such as daily exposure to smoke from wood-fueled cooking fires, has a strongly detrimental effect on long-term health. The mechanisms involved are inflammatory in nature, in that breathing in airborne particles of this nature produces inflammatory signaling that harms tissue function throughout the body, accelerating the onset and progression of all age-related conditions. This is particularly the case for atherosclerosis.

A primary challenge to the study of this correlation between health and particulate air pollution is the confounding effects of wealth and status. Wealthier populations tend to live in areas with lower levels of particulate air pollution, poorer populations in areas with higher levels of particulate air pollution. It is possible to find natural experiments in which the question of wealth is minimized, however. One can look at an interesting paper comparing populations of a similar socioeconomic status in China, for example, showing that higher particulate air pollution correlates with a shorter life expectancy and higher incidence of cardiovascular and respiratory mortality.

Today's research materials are similarly interesting, focused on people who lived in and around Seattle over the past fifty years. This is a small region of the US, but one with enough of a difference in particulate air pollution from site to site to see effects. There is also enough data on income levels and education by location in the Puget Sound to say something about whether or not the burden of particulate exposure falls equally on rich and poor. That said, the way in which this study is constructed leaves open a range of questions about whether the authors have successfully controlled for, say, the effects of medical and public health progress over time since the 1970s. It is worth reading the discussion at the end of the paper in that context.

Fine particulate air pollution associated with higher risk of dementia

Using data from two large, long-running study projects in the Puget Sound region - one that began in the late 1970s measuring air pollution and another on risk factors for dementia that began in 1994 - researchers identified a link between air pollution and dementia. In the study, a small increase in the levels of fine particle pollution (PM2.5 or particulate matter 2.5 micrometers or smaller) averaged over a decade at specific addresses in the Seattle area was associated with a greater risk of dementia for people living at those addresses. "We found that an increase of 1 microgram per cubic meter of exposure corresponded to a 16% greater hazard of all-cause dementia. There was a similar association for Alzheimer's-type dementia."

Fine Particulate Matter and Dementia Incidence in the Adult Changes in Thought Study

Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States. Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based PM2.5 exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-year average PM2.5 exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time.

We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean 10-year average PM2.5 was 10.1 μg/m3. Each 1-μg/m3 increase in the moving average of 10-year PM2.5 was associated with a 16% greater hazard of all-cause dementia. Our results strengthen evidence on the neurodegenerative effects of PM2.5.

CaMKII can be oxidized readily in mammals, but not in flies. This is a small change in DNA sequence, but it produces a greater physical capacity in youth, coupled to a greater vulnerability and loss of tissue function in the environment of chronic oxidative stress characteristic of old age. This is a good example of antagonistic pleiotropy, a concept at the center of the consensus on how evolution reliably leads to the production of species that undergo aging. Individuals that reproduce successfully early in life are favored, and thus mutations - such as CaMKII vulnerability to oxidation - that provide an advantage in youth at the cost of degeneration in later life are readily selected.

The evolutionary conservation of genes that enable the young to run faster and respond robustly to "fight or flight" responses makes sense: It helps them to catch prey or evade predators, thereby ensuring their reproductive success. However, some of these genes carry a steep price that animals need to pay when they grow older. Research shows that turning on CaMKII through a chemical reaction caused by adding oxygen, known as oxidation, strengthens these survival responses for young animals. However, oxidative stress increases with aging, which leads to excessive activation of CaMKII. Elevated CaMKII activity has long been linked to tissue damage seen in heart failure, atrial fibrillation, cancer, lung diseases, and neurodegenerative diseases.

Researchers genetically engineered mice so their CaMKII is resistant to oxidation. They then used mouse-sized treadmills to compare the athletic performance of mice with and without CaMKII oxidation. They found that mice with oxidized CaMKII were able to run, on average, about 150 meters further and about 5 meters per minute faster than the mice with oxidation-resistant CaMKII. Further experiments showed that CaMKII activity in the mouse muscle tissue increased the expression of cellular pathways related to inflammation, diabetes, enlarged heart, seizures, and obesity.

Researchers then used a gene-cutting and insertion tool called CRISPR to add the oxidation site characteristic of mammalian CaMKII to the CaMKII gene in fruit fly DNA, normally lacking that site. In one experiment, the flies were placed into glass tubes and allowed to climb to the top of the tube. The researchers found that flies genetically modified to have the oxidizable CaMKII climbed higher and 5mm per second faster than flies with the oxidation-resistant CaMKII. Despite having better physical performance and cardiac function, the genetically modified flies experienced a more rapid age-related decline and they died at a younger age. The hearts of the genetically modified flies are more vulnerable to damaging effects of excessive oxidants.

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/muscle-protein-that-makes-vertebrates-more-fit-linked-to-limited-lifespan

Researchers recently demonstrated that extracellular vesicles found in urine samples could be used to assess the burden of cellular senescence in the kidneys, and that result most likely correlating well in most individuals with senescent cell numbers throughout the body. The higher the burden of senescent cells, the worse harms caused by their inflammatory secretions, contributing to the onset and progression of many age-related conditions. Here, a similar urine-focused study is undertaken, looking at a different set of molecules found in extracellular vesicles, while also showing that the approach is viable. Given the availability of first generation senolytic drugs, such as the dasatinib and quercetin combination, capable of clearing a fraction of senescent cells from old tissues, a good non-invasive assay is very much needed to show the degree to which the treatments are working.

Extracellular vesicles (EVs) possess properties related to the state of the originating cell, circulate in blood, cerebrospinal fluid, and urine, and provide paracrinehttps://en.wikipedia.org/wiki/Paracrine_signalling">paracrine and remote cell-cell communication messengers. This study investigated whether senescence-associated secretory phenotype (SASP) and immune defense factors in EVs of urine could serve as biomarkers in elderly individuals with and without a comorbidity. Urine samples from young adults and elderly individuals with and without Parkinson's disease (PD) were collected and stored. Urine EVs were separated from a drop-through solution and confirmed by verifying CD9, CD63, CD81, and syntenin expression.

The EVs and drop-through solution were subjected to measurement of SASP cytokines and defense factors. Many SASP cytokines and defense factors could be detected in urinary EVs but not urinary solutions. Elderly individuals (older than 60) had significantly higher levels of the SASP-associated factors IL-8, IP-10, GRO, and MCP-1 in EVs. In contrast, some defense factors, IL-4, MDC, and IFNα2 in EVs had significantly lower levels in elderly adults than in young adults (younger than 30). Patients with and without PD exhibited a similar SASP profile in EVs but significantly lower levels of IL-10 in the EVs from patients with PD.

This study used a simple device to separate urinary EVs from solution for comparisons of SASP and defense mediators between young adults and elders with and without PD. Results from this study indicate that aging signature is present in EVs circulating to urine and the signatures include higher inflammatory mediators and lower defense factors in urinary EVs but not solutions, suggesting a simple method to separate urinary EVs from solutions for searching aging mechanistic biomarkers may make prediction of aging and monitoring of senolytic interventions possible.

Link: https://doi.org/10.1038/s41598-021-95062-y

It has been established that the standard approaches to cancer, chemotherapy and radiotherapy, produce a sizable additional burden of senescent cells in patients. Indeed, forcing cancerous cells into senescence is a desirable goal in cancer treatment, even at the cost of damaging treatments that make many normal cells senescent as well. A lasting, greater burden of senescent cells accelerates the progression of aging in cancer survivors. Thus there is considerable interest in the research community in applying senolytic treatments to destroy senescent cells following cancer therapy, and thus avoid the cost to long-term health, but this strategy is by no means close to adoption in the medical community at the present time.

Immunotherapy is now the standard of care for many forms of cancer in many parts of the world, certainly an improvement over chemotherapy in the short term, but it remains unclear as to what the various forms of immunotherapy will do to patients over the long term. There is certainly the risk of lasting and evident dysregulation of the immune system for a fraction of patients, such as the onset of autoimmunity triggered by treatment. The immune system is important to health, and its age-related decline influences much of the trajectory of late life mortality. Is it the case that most immunotherapy patients are worse off than their peers in later pace of aging as a result of treatment? That remains to be seen.

Functional decline among older cancer survivors in the Baltimore longitudinal study of aging

Evidence has begun to emerge indicating that cancer survivors experience accelerated aging. This study examines this phenomenon by evaluating trajectories of functional decline in older adults with a history of a cancer diagnosis relative to those without a history of cancer.

Community dwelling healthy volunteers in the Baltimore Longitudinal Study of Aging were evaluated. Between 2006 and 2019, 1,728 men and women (aged 22-100) underwent clinical evaluation of functional status; 359 reported having a history of cancer. Longitudinal associations between self-reported cancer history and measures of functional decline were examined using generalized estimating equations. Additionally, time-to-event and Cox proportional hazards models were used to examine trajectories of decline. Where appropriate, age-stratified associations were examined, and models were adjusted for sex, body mass index, race, smoking status, education, and number of comorbid conditions.

Among all participants, a history of cancer was associated with 1.42 greater odds of weak grip strength. Among older participants (older than 65 years of age), those with a history of cancer had 1.61 greater odds of slow gait speed and a 0.11 unit lower physical performance score than those with no cancer history. Time-to-event analysis showed that older individuals with a history of cancer experienced steeper decline in grip strength and gait speed than older adults with no history of cancer. In conclusion, cancer survivors, especially older individuals, demonstrate greater odds of and accelerated functional decline, suggesting that cancer and/or its treatment may alter aging trajectories.

There are at present many programs of medical research and development focused on senescent cells: selectively destroying them, suppressing their inflammatory secretions, or preventing cells from becoming senescent in the first place. The accumulation of senescent cells is an important contribution to degenerative aging, and senolytic treatments that clear a sizable fraction of such cells produce a noteworthy degree of rejuvenation in mice. The first human trials are underway, and soon enough the world will wake to the fact that much of the inflammatory dysfunction of aging can be eliminated by existing, cheap drugs such as the dasatinib and quercetin combination.

With investment money flowing freely into start-ups developing senotherapeutics, and companies like Unity Biotechnology already conducting human trials, Aubrey de Grey is bullish about the sector. "The field of targeting senescent cells has completely exploded. And I would say that it's now become the highest profile area across all the hallmarks of aging. But there's definitely a spectrum of degrees of understanding - there are some people that understand the whole thing really well, and some people who don't."

A simplistic view of the field is that senescent cells are bad for us, and, because there are more of them in older people than there are in younger people, they are associated with aging, so we need to reduce them. "I use the term "death-resistant cells", which doesn't have any connotations about what kind of behaviour the cell is engaging in that is somehow undesirable. It just emphasises the fact that the reason these cells are accumulating, is because the body is failing to get them to commit suicide (apoptosis), which is what normally happens with bad cells."

And de Grey believes that there are "a whole bunch" of questions about how we might go about reducing the number of senescent cells in our bodies. "The most simple way, and something I originally didn't really believe would be possible, is to find drugs that are able to selectively make senescent cells unhappy, and cause them to commit suicide. And it turns out one can find those drugs. The field as a whole is barrelling forward with a wide variety of different synthetic drugs that can induce apoptosis selectively in senescent cells, by a variety of different mechanisms. And that's wonderful. However, pharmaceuticals are always going to have some limitations, they're always going to have some degree of non-selectivity, some toxicity to the cells that we don't want them to kill, and some cells that we do want to kill that they will fail to kill. So it still makes sense for us to consider alternative approaches."

With so much work going on, and so many different ways to tackle the challenge of senescence, there are still no Phase 3 trials in this field. But de Grey believes we're not far away. "I think it's close. Unity Biotechnology are still ahead of the field in terms of progress, the trial that failed last year with a Phase 2 trial, but they've got two other trials in Phase 2 for other indications - they're covering a lot of bases. They're well-funded, they're a really good company, they've got everything going for them, and I think we could be talking no more than a couple of years before we get things through the process."

Link: https://www.longevity.technology/senescence-field-has-completely-exploded/

The open access paper noted here is interesting as a representative example of the way in which researchers presently go about the development of biomarkers of aging that measure biological age, the burden of damage and change that leads to disease and mortality. There is now a great deal of work out there in the literature to build upon, and so much of present progress takes the form of incremental advances that add to the foundation of an established biomarker. It remains the case that all too little exploration is aimed at understand what exactly is being measured, and how the assessed differences are caused by underlying mechanisms of aging.

In this study, we aimed to improve biological age algorithms through a population-risk-based framework. Recent work has introduced a novel measure of 'phenotypic age', developed and validated on NHANES III data. A Gompertz proportional hazards regression was applied to account for the hazard of mortality when selecting clinical biomarkers in the training dataset. This approach is unlike most of the previous biological age algorithms, which largely aimed to model chronological age as the dependent variable. As a result, it is able to capture the association between accelerated biological age and elevated risk of age-related comorbidity.

However, the "phenotypic age" algorithm was unable to establish a significant link between accelerated aging and elevated risk for dementia. We hypothesized that this caveat was not due to the population-risk-framework itself, but because the "phenotypic age" was trained in the NHANES data, which has a relatively younger age distribution than is common for neurological outcomes. Furthermore, we investigated whether by including markers of neurodegeneration, we could improve the prediction of neurological outcomes in advanced-aged cohorts.

Our approach to improve the biological age models comprised of two steps. First, we validated the "phenotypic age" algorithm in the Rotterdam Study. Second, we developed and validated new biological age algorithms in the Rotterdam Study using the same Gompertz proportional hazards regression framework plus neurodegenerative markers (neurofilament light chain, total-tau, amyloid beta-40 and amyloid beta-42). Two variants of a phenotypic blood-based algorithm that either excludes (BioAge1) or includes (BioAge2) neurofilament light chain as a neurodegenerative marker were assessed. BioAge1 and BioAge2 predict dementia equally well, as well as lifespan and healthspan. Each one-year increase in BioAge1/2 was associated with 11% elevated risk of mortality and 7% elevated risk of first morbidities.

Link: https://doi.org/10.1038/s41598-021-95425-5

Atherosclerosis is the build up of fatty plaques in blood vessels, narrowing and weakening them. This leads to heart failure, heart attack, and stroke when vessels or plaques rupture. The core problem is that the macrophage cells responsible for clearing lipids from blood vessel walls become dysfunctional with age. Contributing factors that increase with age include chronic inflammatory signaling that shifts macrophage behavior away from repair activities, and the presence of oxidized lipids that macrophages are poorly equipped to handle. Once a plaque is established, these mechanisms ensure that it becomes an inflammatory hot spot that attracts and kills ever more macrophages, growing as a result.

Mitochondria, the power plants of the cell, become dysfunctional with age. This dysfunction can be connected, at least in principle, to the important contributing mechanisms of atherosclerosis. This is the topic of discussion in today's open access review paper. Whether mitochondrial aging makes inflammation worse in ways that matter to atherosclerosis is an interesting question; as is usually the case, the mechanisms exist, but one can certainly debate the degree to which they matter versus other mechanisms. More defensible is the rising level of oxidative stress with age, largely the result of mitochondria generating ever more oxidizing molecules as a side-effect of changes in their operation. This leads to increased oxidization of lipids, and thus more of a burden of toxicity due to those oxidized lipids, falling heavily on macrophages.

How much of a benefit can one obtain in the case of atherosclerosis by rejuvenating mitochondrial function? That is hard to say, as ever, without a proof of concept study. On the inflammation side of the house, there is evidence to suggest that broad suppression of inflammatory signaling produces little more benefit to patients than does the lowering of blood cholesterol, however. That might indicate that oxidized lipids are responsible for a larger fraction of the problem of cardiovascular mortality, but again, until someone (such as the Underdog Pharmaceuticals or Repair Biotechnologies teams) provides evidence based on specifically and only removing oxidized lipids, it is hard to do more than hypothesize.

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

Cardiovascular disease (CVD) is the main cause of death worldwide. Atherosclerosis is the underlying pathological basis of CVD. Mitochondrial homeostasis is maintained through the dynamic processes of fusion and fission. Mitochondria are involved in many cellular processes, such as steroid biosynthesis, calcium homeostasis, immune cell activation, redox signaling, apoptosis, and inflammation, among others. Under stress conditions, mitochondrial dynamics, mitochondrial cristae remodeling, and mitochondrial reactive oxygen species (ROS) production increase, mitochondrial membrane potential (MMP) decreases, calcium homeostasis is imbalanced, and mitochondrial permeability transition pore (mPTP) open and release of mitochondrial DNA (mtDNA) are activated.

mtDNA recognized by TLR9 can lead to NF-κB pathway activation and pro-inflammatory factor expression. At the same time, TLR9 can also activate NLRP3 inflammasomes and release interleukin, an event that eventually leads to tissue damage and inflammatory responses. In addition, mitochondrial dysfunction may amplify the activation of NLRP3 through the production of mitochondrial ROS, which together aggravate accumulating mitochondrial damage.

In addition, mtDNA defects or gene mutation can lead to mitochondrial oxidative stress. Mitochondria are highly dynamic organelles that constantly produce adenosine triphosphate (ATP). Events, such as mtDNA mutation, imbalance in calcium homeostasis, accumulation of oxidative stress products, and metabolic dysfunction are hallmarks of mitochondrial damage. When mitochondria are damaged or dysfunctional, energy production is limited and large quantities of ROS are produced. Increased ROS levels induce endothelial dysfunction, vascular inflammation, and accelerated accumulation of oxidized low density lipoprotein (ox-LDL) in the arterial wall, a phenomenon that promotes atherosclerosis.

Finally, obesity, diabetes, hypertension, and aging are risk factors for the progression of CVD, which are closely related to mitochondrial dynamics. Mitochondrial dynamics may represent a new target in the treatment of atherosclerosis. Antioxidants, mitochondrial inhibitors, and various new therapies to correct mitochondrial dysfunction represent a few directions for future research on therapeutic intervention and amelioration of atherosclerosis.

TDP-43 is one of the few proteins in the body that can misfold in ways that lead to solid aggregates that disrupt cell and tissue function. The biochemistry and relevance of TDP-43 is a more recent area of research in comparison to the study of, say, amyloid-β in Alzheimer's disease and α-synuclein in Parkinson's disease, but it appears important to the progression of a number of neurodegenerative conditions. Researchers here elaborate on the relationship between TDP-43 and age-related demyelination, the corrosion of myelin sheathing around axons that is necessary for nervous system function, normally maintained by a population of cells known as oligodendrocytes. Extreme demyelination leads to ultimately fatal conditions such as multiple sclerosis, but occurs to a lesser yet still harmful degree in normal aging, contributing to cognitive decline.

The TDP-43 protein is linked to multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 plays many vital roles within cells, but, under certain circumstances, it can clump together to form toxic aggregates that damage cells and prevent TDP-43 from performing its normal functions. TDP-43 aggregates are found in the brains of most ALS patients and ~45% of FTD patients and are also linked to several other neurodegenerative disorders, including some cases of Alzheimer's disease. The aggregates form not only in neurons, but also in other brain cell types such as oligodendrocytes. These latter cells protect neurons and speed up the transmission of nerve impulses by wrapping neurons in a fatty substance called myelin.

Researchers have previously shown that oligodendrocytes need TDP-43 to survive and wrap neurons in myelin. In the new study, researchers find that one reason oligodendrocytes are dysfunctional in the absence of TDP-43 is that they are unable to synthesize or take up the cholesterol they need to sustain myelin production.

Cholesterol is such a major component of myelin that 25% of the body's total cholesterol can be found in the central nervous system. Oligodendrocytes are known to synthesize large amounts of cholesterol for themselves, but they can also acquire it from other brain cells called astrocytes. Researchers determined that, in the absence of TDP-43, oligodendrocytes lack many of the enzymes required to synthesize cholesterol, and also have reduced levels of the low density lipoprotein receptor that can take in cholesterol from outside the cell. Supplementing these TDP-43-deficient cells with cholesterol restored their ability to maintain the myelin sheath.

Similar defects in cholesterol metabolism may occur in patients, where the formation of aggregates might prevent TDP-43 from performing its normal functions. Researchers analyzed brain samples from FTD patients and found that their oligodendrocytes produced lower amounts of two key enzymes required for cholesterol synthesis, while the low density lipoprotein receptor was incorporated into TDP-43 aggregates.

Link: https://www.eurekalert.org/news-releases/923747

Insilico Medicine works on cost reduction and acceleration of existing small molecule drug discovery approaches via machine learning and other forms of automation. While starting out as an aging-focused company, their primary goal at this stage, steered by their investors, is to sell the software platforms they produce to the pharmaceutical industry. Their in-house drug development programs serve as marketing for this goal. Those they chose to publicize are somewhat senotherapeutic in nature at the present time, focused on clearance or suppression of senescent cells to treat fibrosis. A range of evidence suggests that senescent cells are largely responsible for the malfunctions of normal tissue maintenance and regeneration that cause fibrosis, the inappropriate deposition of scar-like structures in many aged organs that harm tissue function. Since there are no good therapies to address fibrosis at this time, a number of ongoing senotherapeutic programs in industry and academia target one or more fibrotic diseases in order to maximize the chances of regulatory approval and thus commercial success.

Insilico Medicine, a global company specializing in the applications of the next-generation machine learning technologies for drug discovery and development, announced today that its AI-powered drug discovery platform had delivered a preclinical candidate for kidney fibrosis. Chronic kidney disease affects 10 percent of the world's population, and, unfortunately, it has no cures or efficacious drugs on the market. Kidney fibrosis is the common pathogenesis in the progression of chronic kidney disease ("CKD") and is a major unmet medical need. Approximately 850 million people worldwide have kidney disease often being driven by or associated with kidney fibrosis. We are very excited to see that our AI-powered drug discovery engine has managed to uncover novel targets and novel molecules that have demonstrated preclinical efficacy in kidney fibrosis"

Insilico Medicine achieved a great breakthrough in February 2021 when it announced that its AI system identified a novel drug target and novel compound to treat idiopathic pulmonary fibrosis, which is another fibrotic disease affecting patients worldwide with high unmet medical needs. What also made the discovery noteworthy was that this was achieved within 18 months and a $2.6 million budget. Repeating that success, Insilico Medicine leveraged its platforms to develop the target hypothesis for kidney fibrosis and generate compounds with drug-like properties. The compound that markedly inhibited the development of fibrosis and significantly improved myofibroblast activation are critical for tissue repair and wound healing. Insilico Medicine plans to complete the IND-enabling studies for this program in 2022.

Link: https://www.eurekalert.org/news-releases/924480

The aging of the vasculature has detrimental effects on organs throughout the body. The most structurally apparent issue is that of atherosclerosis, the buildup of fatty deposits that narrow and weaken blood vessels. This ultimately leads to heart failure, stroke, heart attack, and death. A close second is the stiffening of blood vessels, due to a variety of processes such as cross-linking to reduce elasticity in blood vessel walls, and inflammation-linked disruption of the vascular smooth muscle tissue responsible for contraction and dilation of blood vessels. This stiffening causes raised blood pressure, which in turn produces pressure damage in sensitive tissue throughout the body, and raises the risk of atherosclerotic lesions rupturing.

Further, and separately, the density of capillary networks is reduced with age. Hundreds of capillaries pass through every square millimeter of tissue cross-section in muscle alone, necessary to provide sufficient nutrients in an environment in which perfusion based transport is limited to a millimeter of distance at most. The dysfunctions of age cause a declining maintenance of these small scale blood vessel networks, which is thought to impair cell and tissue function by limiting the supply of nutrients.

In today's research, scientists attempt to address this problem via upregulation of VEGF expression, using a gene therapy approach. VEGF levels decline with age, and this is thought to be involved in the reduction in capillary network maintenance, though this layer of regulation of activity is some distance downstream from root causes of age-related change. In effect, upregulation is a compensatory approach, overriding some of the normal reaction of the molecular damage of aging.

It is interesting that this works well in mice, as a major challenge in controlling the processes of angiogenesis, the name given to the creation of new blood vessels, is that these processes are very complex. Different signals and cells are involved in different roles and different amounts at different stages, and bluntly upregulating just one component part of it tends to result in a poor outcome, such as the generation of incompletely constructed, leaky blood vessels. This is in fact what happens in wet macular degeneration, a matter of excessive malformed blood vessel growth in the retina due to the localized presence of too much VEGF, one of the peculiarities of this age-related condition. Biochemistry is complicated, and the details of any intervention matter!

Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span

All body cells rely on blood vessels (BVs) for the provision of oxygen and other blood-borne substances and, in certain settings, also for the provision of endothelial-derived paracrine factors. Like other organ systems, the vascular system undergoes aging, which leads to progressive functional deterioration. Given the centrality of BVs to organ homeostasis, it has been hypothesized that vascular aging is an upstream, founding factor in organismal aging, but experimental support for this proposition is limited. Vascular aging involves both large and small vessels, with the latter marked by capillary rarefaction, i.e., age-related failure to maintain adequate microvascular density (MVD). A key homeostatic mechanism preventing MVD reduction relies on the angiogenic activity of vascular endothelial growth factor (VEGF), which by virtue of its hypoxic inducibility, constantly acts to replenish lost vessels and match vascular supply to the tissue needs. The reasons that VEGF fails to do so during aging is unknown.

Compromised vascular function is expected to perturb organ homeostasis in ways conducive for the development of age-related frailties and diseases. Accordingly, counteracting critical facets of vascular aging might be a useful approach for their alleviation. The presumption that insufficient vascular supply in aging is underlined by VEGF signaling insufficiency, primarily (but not exclusively) because of its indispensable role in preventing capillary loss, led us to investigate whether securing a young-like level of VEGF signaling might rectify capillary loss and its sequelae. On the premise that deteriorated vascular function is an upstream driver of multiorgan malfunctioning, it is envisioned that its rectification might confer comprehensive geroprotection.

Although VEGF production is not significantly reduced during mouse aging, longitudinal monitoring revealed that VEGF signaling was greatly reduced in multiple key organs. This was associated with increased production of soluble VEGFR1 (sVEGFR1) generated through an age-related shift in alternative splicing of VEGFR1 mRNA and its activity as a VEGF trap. A modest increase of circulatory VEGF using a transgenic VEGF gain-of-function system or adeno-associated virus (AAV)-assisted VEGF transduction maintained a more youthful level of VEGF signaling and provided protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice. Conversely, VEGF loss of function in endothelial cells accelerated the development of these adverse age-related phenotypes. VEGF-treated mice lived longer and had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle loss (sarcopenia) associated with better preservation of muscle-generating force, reduced bone loss (osteoporosis), reduced kyphosis, and reduced burden of spontaneous tumors.

Researchers have in recent years put forward contradictory evidence for and against a role for persistent infection, such as by herpesviruses, in neurodegeneration and the incidence of Alzheimer's disease. The Alzheimer's disease scientific community is in need of a good explanation as to why only some people with the known risk factors go on to develop the condition. That disease incidence in fact depends on the burden and duration of persistent infection would be a convenient answer, if true. It is often the case that contradictory evidence means that better segmentation of the population of interest is required. Along these lines, researchers here suggest that infection is more of a contributing cause to Alzheimer's disease in people with the APOE4 allele that confers a greater risk of Alzheimer's disease. About a quarter of all people have one copy of APOE4.

Several studies have suggested the implication of infectious agents in Alzheimer's disease (AD) pathophysiology with herpes simplex virus type 1 (HSV-1) being one of the most investigated candidates. In fact, the implication of HSV-1 could potentially explain the location, chronology, and the type of damage described in AD. First, HSV-1 is a neurotropic virus with a particular tropism for the temporal cortex, as shown by the localization of lesions in HSV-1 encephalitis and postmortem studies highlighting the presence of HSV DNA in the brains of older adults. HSV-1 also has the ability to move from neurons to neurons, which could explain the progression of lesions to other brain areas.

Second, HSV-1, which remains in a latent state throughout life after primary infection, can periodically reactivate during a temporary immune decline. With advancing age, the development of a long-lasting immunosenescence may allow more frequent and/or more intense reactivations of the virus, thereby explaining the progressive and relatively late onset of AD. Finally, HSV-1 could be linked to genetic risk factors of AD, especially APOE4. The existence of such genetic susceptibility factors could explain why, despite a seroprevalence of ~80% in the elderly, some infected individuals remain "healthy carriers", while others develop clinical consequences of the infection.

Our findings suggest an increased risk of AD in subjects infected by HSV. Infected subjects with an anti-HSV IgG level in the highest tercile (possibly reflecting more frequent reactivations over time) had lower hippocampal volume (HV) compared to uninfected subjects. Infected subjects presented also more microstructural alterations of the parahippocampal cingulum and fornix. Our results are also in favor of an interaction between being infected with HSV and APOE4 status regarding advanced markers of the disease (HV and then incidence of AD). Among APOE4 carriers, infected subjects presented lower HVs, although not significant, and had a two times higher risk of developing AD and a three times higher risk if their anti-HSV IgG level was in the highest tercile. Among APOE4 noncarriers, no associations were observed between HSV status and HV or incidence of AD.

Link: https://doi.org/10.1038/s41398-021-01532-2

Bringing degenerative aging under medical control, ending the tens of millions of deaths each year, ending the suffering of hundreds of millions more. This is a plausible goal for our era of biotechnology. Yet even as the first rejuvenation therapies have become a reality, in the form of first generation senolytic drugs that clear a sizable fraction of senescent cells from the body, there is little public enthusiasm for - and understanding of - the path ahead to a better world. A world in which people have the choice not to decay in body and mind as they gather wisdom and experience in later life. Change is in the air, but it is far too slow, and every year of delay just adds to the toll of suffering and death that is the present human condition.

Today, some two thirds of all human funerals owe to the processes of aging. Only 3.7 per cent of cancer patients are under thirty-four, and if a cure for all types of cancers were miraculously found, it would add no more than two years to the average human lifespan, because other age-related diseases would still take their toll. But while the term "pandemic" - from the Greek pán ("all") and dēmos ("people") - does not imply infectious disease, our ethics prevent us from applying it to the nearly 100,000 daily deaths caused by aging.

Yet in 2021, we all agree that the effects of aging must be treated. The United States alone spends over $300 billion taxpayer dollars each year on the treatment of patients with Alzheimer's, and the trillions of dollars spent on the age-related mortality risk of COVID-19 by this single country, in this single year, make for a painful calculation. But to preventively fund aging research itself goes beyond the reactive purview of both politics and medical systems.

When asked in a 2013 Pew Research Center survey, 56 per cent of Americans replied they would not want to slow their aging and live up to 120. At first glance, their logic is sound: with an unaltered average health-span, to add another forty years to average human lifespan could be catastrophic, for both individuals and governments. By 2035, demographics in the United States will reach a turning point, with more people in the country aged 65 or older than 18 or younger.

At second glance, however, the Pew survey respondents are the same Americans who, if diagnosed with early signs of Alzheimer's, would do all within reach to slow down its progression. In reality, one cannot successfully slow down the processes of aging without also increasing healthspan. And in techno-progressive societies, a larger number of healthy, long-lived individuals are more likely to mend financial structures than to burden them.

We think of aging as the product of this orphic thing called "time", ignoring that species far less resourceful than ours live on for centuries longer, and some (like the American lobster) do not decrease in strength, do not have their metabolism slowed down, and become more rather than less fertile, with the passage of time. Surely, we can do better than to draw a skewed, myopic ethics, which enshrines human life, even as we treat the biological processes of aging like a mystical, tabooed concept, from which life's meaning is to be derived. When some two thirds of human deaths owe to the effects of aging - a number rapidly increasing with advancements in robotics, vaccines, and self-driving cars - it becomes difficult to argue that death and aging must be recognised as divorced processes.

Link: https://www.abc.net.au/religion/should-we-engineer-ourselves-out-of-aging/13479746

Macrophage dysfunction is the crucial central issue in atherosclerosis, the ultimately fatal buildup of fatty lesions in blood vessel walls. Macrophages are the innate immune cells responsible for clearing out inappropriate lipid deposition in blood vessel walls, returning those lipids to the bloodstream. With age, rising levels of inflammatory signaling and toxic, oxidized lipids cause macrophages to falter at this task. Macrophages in the vicinity of growing atherosclerotic lesions become inflammatory foam cells and die, adding to the lesion while attracting more macrophages to the same fate.

The best approach to a cure for atherosclerosis is to intervene in macrophage function, but this is so far an underfunded and underappreciated part of the field. If macrophages can be made resilient to the factors that force them into dysfunction, then they should return to the task at hand, functioning as they did in youth, and reverse the development of atherosclerotic lesions. There are, unfortunately, few research programs focused on this goal, and only a couple of biotech companies (such as Underdog Pharmaceuticals and Repair Biotechnologies) undertaking relevant preclinical programs. So it is always interesting to see a greater diversity of progress on this front, even if the work here appears to be somewhat removed from the root causes of macrophage dysfunction, and is focused on downstream issues within cell metabolism.

Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis

Despite significant advances in diagnosis, drug development, and medical treatment, cardiovascular diseases (CVDs) remain a leading cause of death worldwide. Atherosclerosis, the underlying cause of most CVDs, is a chronic disease of the arteries arising from imbalanced lipid metabolism, a maladaptive immune response, and dysregulated redox homeostasis. While the association between altered lipid metabolism and CVDs is well established, recent evidence indicates that dysregulated metabolism of specific amino acids plays an important role in the pathogenesis of atherosclerosis. Among all amino acids, lower circulating glycine is emerging as a common denominator in CVDs and related metabolic comorbidities, including coronary heart disease, myocardial infarction, obesity, type 2 diabetes (T2D), metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). While numerous studies reported lower circulating glycine in cardiometabolic diseases, the contribution of impaired glycine metabolism to the development of atherosclerosis remains unclear.

Glycine is the simplest, nonessential amino acid and is synthesized primarily in the liver from serine, threonine, alanine, and glyoxylate. Impaired biosynthesis of glycine in atherosclerosis was suggested by evidence of a decreased glycine/serine ratio in plasma from patients with unstable atherosclerotic plaques. Furthermore, transcriptomics of human and mouse livers revealed suppression of genes driving glycine biosynthesis in NAFLD, predominantly alanine-glyoxylate aminotransferase (AGXT). AGXT is expressed primarily in the liver where it catalyzes glycine biosynthesis from alanine and glyoxylate. Functional deficiencies of AGXT lead to accumulation of glyoxylate, which is rapidly converted to oxalate. Whereas limited literature proposed that dysregulated oxalate metabolism is linked to CVDs, the role of this metabolic pathway in the pathogenesis of atherosclerosis has not been studied yet.

In this study, using targeted metabolomics, we identified decreased ratios of glycine to its precursors or related metabolites, serine, threonine, and oxalate, in patients with coronary artery disease (CAD). As found in patients with CAD, the glycine/oxalate ratio was significantly decreased in atherosclerotic Apoe-/- mice that showed suppression of hepatic AGXT. Utilizing genetic and dietary approaches to manipulate oxalate in Apoe-/- mice combined with studies in isolated macrophages, we demonstrate that increased oxalate exposure drives accelerated atherosclerosis in relation with dysregulated redox homeostasis, an increased inflammatory response, and enhanced hypercholesterolemia. The therapeutic potential of targeting dysregulated oxalate metabolism in atherosclerosis was studied using adeno-associated virus (AAV)-mediated overexpression of AGXT in Apoe-/- mice that showed lower oxidative stress, inflammation, and atherosclerosis. Thus, by studying impaired glycine metabolism in patients and mice with atherosclerosis and using mouse models to manipulate oxalate, we identified dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.

Much of cell signaling is carried via extracellular vesicles, membrane-wrapped packages of molecules. Researchers are finding that delivery of extracellular vesicles harvested from stem cells may be a good replacement for first generation stem cell therapies, in which the transplanted cells produce benefits via signaling before dying. Extracellular vesicles are an easier, cheaper approach from a logistical point of view. Here, researchers show that only vesicles generated by stem cells from young mice are capable of producing an impact on frailty in old mice, an indication of the degree to which aging impacts cell signaling and function.

Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement.

ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. The metabolome of treated mice changed to a youth-like pattern. Very interestingly, the effect of ADSCs-sEVs seems to be finite, as we observed in a more long-term experiment that the effect on the functionality of old mice was lost two months after treatment with ADSC-sEVs. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

Link: https://doi.org/10.1101/2021.07.29.454302

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. A little of the telomere length is lost with each cell division. A somatic cell with short telomeres ceases replication, and usually self-destructs. All cancers must thus continually lengthen telomeres in order to engage in unfettered replication and growth. This makes interference in telomere lengthening an attractive strategy as the basis for a truly universal cancer therapy. A few research and development programs have this in mind, most of which are focused on the role of telomerase in telomere lengthening. There are alternative lengthening of telomeres (ALT) mechanisms which operate in some cancers, however. Dealing with telomerase alone solves only a majority of the problem. Unfortunately, finding an approach to interfering in ALT is an area of research with little support, and which is consequently moving very slowly. So it is always interesting to see news from that part of the field.

About 10-15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored.

Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA.

Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.

Link: https://doi.org/10.1186/s13578-021-00660-y

Senescent cells accumulate with age throughout the body, and disrupt tissue structure and function via their inflammatory sections. Work on senolytic drugs capable of clearing senescent cells from aged tissues has in recent years pointed to cellular senescence in the supporting glial cells of the brain as an important mechanism in neurodegenerative conditions. Clearing a sizable fraction of senescent microglia and astrocytes in mouse models of tauopathy reduces harmful tau aggregation and neuroinflammation, a promising result. The senolytic treatment used, the combination of dasatinib and quercetin, both of which pass the blood-brain barrier, will soon be used in a human trial with Alzheimer's patients. I've suggested in the past that it seems plausible at this point that the best Alzheimer's therapy of the next decade or two will be some form of senolytic treatment.

Today's popular science coverage discusses work that points to a bidirectional relationship between pathological tau aggregation, characteristic of the late stage of Alzheimer's disease, and the accumulation of senescent glial cells in the brain. It isn't just that senescent cells provoke an inflammatory state that encourages tau aggregation, but also that tau aggregation leads to more cells becoming senescent. There is considerable debate over how exactly Alzheimer's emerges in its early stages, but researchers are more agreed that later stages of the condition have the look of a runaway feedback loop between cellular senescence and other forms of pathology in the brain, such as tau aggregation. Senolytic drugs may well turn out to be a good way to interfere in that process in humans; we'll know whether or not this is the case a few years from now.

Astrocytes Are Just Dying to Spread Tau

Scientists had previously reported that removing senescent glia from mouse models of tauopathy protected them from neurodegeneration. But what made those glia senescent to begin with? Researchers now claim it was tau. They detail how tau oligomers inflamed astrocytes in culture, prompting them to expel a protein called high mobility group box 1 (HMGB1). HMGB1 then led adjacent cells down the path to senescence. Inhibiting HMGB1 release prevented this culture of corruption and, in mouse models of tauopathy, it not only reduced senescent astrocytes but also the amount of tau oligomers and tangles. The animals' short-term memory also improved.

HMGB1 is a nuclear protein involved in DNA replication and repair. Its appearance in the cytosol signals cellular senescence. Released by glia, it can activate nearby cells to crank out inflammatory cytokines, ultimately damaging tissue through a process called senescence-associated inflammation. Researchers previously found HMGB1 in the cytosol of astrocytes that were surrounded by tau oligomers in Alzheimer's disease (AD) and frontotemporal dementia (FTD) postmortem tissue. Did HMGB1 relocalization within astrocytes indeed indicate senescence and contribute to tau pathology?

To find out, researchers examined frontal cortex tissue taken postmortem from eight people who had had AD, six people who had FTD, and eight age-matched controls. In the AD and FTD samples, 75 percent of astrocytes were senescent and had oligomers of tau within or nearby. Researchers found HMGB1 in their cytoplasm. Did the oligomers cause senescence? To find out, the researchers cultured astrocytes from healthy wild-type mice and treated them with oligomers made from recombinant human tau. The astrocytes took up the oligomers. Eleven days later, HMGB1 had turned up in the cytoplasm, ultimately escaping into the culture medium. Seventy percent of the tau-exposed astrocytes also expressed p16 and had high β-gal activity.

Would inhibiting HMBG1 release from cells have any benefit in the brain? To find out, researchers treated 12-month-old hTau mice with ethyl pyruvate (EP) and glycyrrhizic acid (GA), two inhibitors of HMGB1 release, three times a week for eight weeks. These mice express six isoforms of human tau and have significant tangles, gliosis, neurodegeneration, and cognitive problems by 1 year of age. Compared to control mice, inhibitor-treated mice were more curious about new objects and environments, hinting that their short-term memory had improved. In keeping with this, the treated mice had fewer tangles and less phosphorylated tau in the hippocampus.

There is good evidence for physical activity to improve cognitive function, particularly memory, both in the short term following a bout of exercise and over the long term as a result of regular exercise. Researchers here take the approach of measuring biomarkers known to be linked to cognitive function, and find that, as expected and shown elsewhere, they are improved by a program of structured exercise in older people.

Researchers tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health. They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilized to understand biochemical pathways that may be affected by Alzheimer's disease (AD).

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.

Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the "aeRobic Exercise And Cognitive Health (REACH) Pilot Study". The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.

Results showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training. Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho. The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia. Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingolipids, and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.

Link: https://www.fau.edu/newsdesk/articles/biomarkers-exercise-dementia.php

There are any number of studies to demonstrate that older people are more sedentary than they can be or should be, and that this lack of physical activity has a meaningful negative impact on health and mortality risk. In this example, researchers report on the improved functional status observed in a study population as a result of lifestyle interventions such as structured exercise programs. We happen to be fortunate enough to live in an era of comparative comfort and indolence, enabled by progress in technology. It is up to the individual as to whether or not to accept the incidental harms along with the considerable benefits of progress. Being sedentary is a choice for the vast majority of those who live that lifestyle.

The socioeconomic and health consequences of our ageing population are well documented, with older adults living in long-term care facilities amongst the frailest possessing specific and significant healthcare and social care needs. These needs may be exacerbated through the sedentary behaviour which is prevalent within care home settings. Reducing sedentary time can reduce the risk of many diseases and improve functional health, implying that improvements in health may be gained by simply helping older adults substitute time spent sitting with time spent standing or in light-intensity ambulation.

This study identified the impact of 1 year of lifestyle intervention in a group of older adults living in a long-term care setting in Italy. One hundred and eleven older adults (mean age, 82.37 years) participated in the study. Sixty-nine older adults were in the intervention group (35 without severe cognitive decline and 34 with dementia) and 42 older adults were in the control group. Data on physical functioning, basic activities of daily living (BADL) and mood were collected 4 times, before, during (every four months) and after the 1 year of intervention. The lifestyle intervention focused on improving the amount of time spent every week in active behaviour and physical activity (minimum 150 min of weekly activities).

All participants completed the training program and no adverse events, related to the program, occurred. The intervention group showed steady and significant improvements in physical functioning and a stable situation in BADL and mood following the intervention in older adults with and without dementia, whilst the control group exhibited a significant decline over time. These results suggest that engagement in a physical activity intervention may benefit care home residents with and without dementia both physically and mentally, leading to improved social care and a reduced burden on healthcare services.

Link: https://doi.org/10.3390/ijerph18147612

Major depressive disorder, more commonly known as depression, is all too prevalent a part of the human condition. Like many aspects of brain function, a great many layered mechanisms are investigated and debated by the research community, while still being poorly understood as a whole. Pharmaceutical treatments for depression are actually quite good for those people that they work for, but finding the right treatment can be a haphazard, experimental journey of years and different approaches for those who suffer. We might suspect that these treatments are essentially compensatory in nature, touching on mechanisms (such as serotonin levels) that are somewhat downstream from root causes.

That regular exercise reliably helps with depression is evidence for both inflammation and BDNF levels to be important, for their effects on neurogenesis among other mechanisms. Exercise reduces inflammation, and increases BDNF levels in the brain. But why do only some people need exercise in order to evade depression? Firm answers remain a challenge due to an incomplete understanding of the biochemistry of depression, or, for that matter, of much of the way in which the brain gives rise to the mind.

As pointed out by the authors of today's open access paper, depression in later life has a worse prognosis. This again points towards the role of inflammation and BDNF levels. With age, people exhibit a rising level of chronic inflammation. Some of this is avoidable, such as the inflammation originating from excess levels of visceral fat accompanying weight gain. Some of it is not, deriving from the aging of the immune system and molecular damage to tissues. BDNF levels decline with age, and one of the identified contributions to this decline is a changing gut microbiome, leading to reduced production of metabolites such as butyrate that enhance BDNF levels.

Molecular Basis of Late-Life Depression

Late-life depression, compared to depression at a young age, is more likely to have poor prognosis and high risk of progression to dementia. A recent systemic review and meta-analysis of the present antidepressants for late-life depression showed that the treatment response rate was 48% and the remission rate was only 33.7%, thus implying the need to improve the treatment with other approaches in the future.

Recently, agents modulating the glutamatergic system have been tested for mental disorders such as schizophrenia, dementia, and depressive disorder. Ketamine, a noncompetitive NMDA receptor (NMDAR) antagonist, requires more evidence from randomized clinical trials (RCTs) to prove its efficacy and safety in treating late-life depression. The metabotropic receptors (mGluRs) of the glutamatergic system are family G-protein-coupled receptors, and inhibition of the Group II mGluRs subtypes (mGlu2 and mGlu3) was found to be as effective as ketamine in exerting rapid antidepressant activity in some animal studies.

Inflammation has been thought to contribute to depression for a long time. The cytokine levels not only increase with age but also decrease serotonin. Regarding late-life depression, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) released in vivo are likely to contribute to the reduced serotonin level. Brain-derived neurotrophic factor (BDNF), a growth factor and a modulator in the tropomyosin receptor kinase (Trk) family of tyrosine kinase receptors, probably declines quantitatively with age. Recent studies suggest that BDNF/TrkB decrement may contribute to learning deficits and memory impairment.

In the process of aging, physiological changes in combination with geriatric diseases such as vascular diseases result in poorer prognosis of late-life depression in comparison with that of young-age depression. Treatments with present antidepressants have been generally unsatisfactory. Novel treatments such as anti-inflammatory agents or NMDAR agonists/antagonists require more studies in late-life depression. Last but not least, late-life depression and dementia, which share common pathways and interrelate reciprocally, are a great concern. If it is possible to enhance the treatment of late-life depression, dementia can be prevented or delayed.

This open access paper discusses a secondary issue in the aging of the adaptive immune system. Of primary concern is that the supply of new T cells diminishes over time, due to the atrophy of the thymus where such cells mature, as well as due to issues in the hematopoietic system of the bone marrow where such cells are produced. As noted here, a secondary concern is that the population of unspecialized naive T cells needed to respond effectively to novel threats begins to have issues maintaining itself in readiness. So not only is the supply of new naive T cells reduced to a tiny fraction of youthful levels, but the population present at any given time corrodes into ineffectiveness more rapidly.

A key feature of age-related immune erosion (termed "immune aging") is the loss of naïve T cells. This loss is often attributed to the involution of the thymus during adulthood however naïve T cells can be maintained for decades by homeostatic proliferation within lymph nodes and secondary lymphoid tissues. Naïve cell loss is instead caused by a breakdown in peripheral homeostasis during the aging process. Naïve T cell homeostasis is multi-faceted, requiring both cell survival and the retention of a quiescent state. Recent studies in humans highlight that naïve cells not only decline numerically in lymph nodes, but they also break quiescence, acquiring a distinct, partially differentiated state during aging.

Stem cell quiescence is a reversible state of growth arrest that plays an important role in tissue homeostasis and regeneration. Recent work in the area of stem cell biology has established that quiescence is not a passive process but is actively maintained by transcriptional and post-transcriptional regulation, including chromatin modification and microRNA-mediated gene repression. Notably, there are distinct levels of stem cell quiescence, ranging from 'deep' to 'shallow' that correlated with more rapid responses and altered functional capacity in both mice and man.

Biologically, naïve T cells are relatively similar to quiescent stem cells, particularly in their high pluripotency and proliferative potential. However, unlike stem cells, the extracellular cues for exit from quiescence are unique to naïve T cells. These cells classically retain a quiescence state until they encounter a specific antigen within their local lymph node niche. Upon direct antigen activation, naïve T cells exit quiescence, rapidly proliferate and can differentiate into numerous functional states depending on numerous factors including the local cytokine and cellular milieu.

In turn, the regulation of activation and the maintenance of cellular quiescence in T cells is extremely important for immune homeostasis, as its failure can lead to significantly perturbed immunity, such as autoimmune disease, cancer, or increased infection. In aging, proliferation capacity of naïve T cells appears intact however pluripotency is diminished; naïve T cells from older individuals display reduced ability to form memory and skewing of subset polarization. These data collectively suggest a partial breakdown in cellular quiescence.

Link: https://doi.org/10.20900/agmr20210015

George Church is a noted geneticist, involved in a number of gene therapy projects that relate to aging in some way - though largely through manipulation of metabolism to slow aging rather than by directly attacking the root causes of aging. Gene therapy tends to lend itself to adjustment of cellular metabolism first and foremost, raising or lowering expression of regulatory proteins, but there are certainly ways in which it can be used to produce repair of damage rather than changes in cell behavior to override reactions to that damage. Church is clearly one of those who thinks that the viable path for aging is to produce incremental gains via adjustment of metabolism to look more like that of very long-lived species. This is more or less the polar opposite of the SENS view on the road to human rejuvenation via repair of the underlying cell and tissue damage that causes aging.

Do we have any successes with gene therapy specifically in the rejuvenation field?

That's a little further out. I mean, most are in pre-clinical animal trials or in very tiny, not yet approved human trials. But yes, pre-clinical animal trials are looking good. We published two papers, one on three genes that spread from the site to which they were delivered systemically, and another one about three genes that are localized; these are the so-called Yamanaka factors that cause rejuvenation. Those are two different studies.

Therapies for animals is something that one of your many start-ups, Rejuvenate Bio has been doing. Recently, it has secured another 10 million in funding, and it has been alive for a few years, so what is the situation there?

Rejuvenate Bio was involved in both of those papers, and those were both in mice, and they since have taken one of those two combination gene therapies, three different genes, things like fibroblast growth factor (FGF21), the soluble form of the TGFß receptor, and aKlotho. Anyway, that three-gene combination has then been moved into dog trials. So, this is not an animal model, this is an actual veterinary product, because people do care quite a bit about their pets.

Do you think an abundance of private initiative is the way to go when it comes to fighting aging, or maybe governments should play a greater role?

I think, and some of my colleagues agree, that we need to re-educate the FDA to be more interested in preventative medicine and in aging as a disease, and I think that's a fine goal, but that could take time, and that's uncertain. I think it's easier and probably better to just accept that something that works on the core, fundamental components of aging will also reverse several different types of diseases simultaneously. We are working on eight different diseases. In a way, diseases of aging are even better than biomarkers, because they are really what we care about. That doesn't require the FDA to think revolutionary new thoughts or wrap their heads around something strange. It also has advantages over preventative medicine. I love preventative medicine, we work on it, but to convince a cautious federal agency to give a dose of something powerful to someone who is already healthy...

So, most preventative medicine has been very benign, a very "do no harm" sort of thing. But in this case, if you work on eight different diseases of aging, and some of them have a fairly early onset, and you can actually show reversal, you will get approval. Then you will have, as a side benefit, preventing all the other diseases. You will not only cure the early-onset disease, you will prevent all the others. That is, if you have the right thing.

Do we even know how to aim at life extension?

I don't think we do. I think if we get serious aging reversal, it's something that we can continue to improve on, just like we improved on transportation from the first wheel to rocket ships, or the way we moved from being able to sequence a few base pairs of DNA to being able to sequence the entire biosphere. The thing is to get the foot in the door where we're actually working on the core processes of aging, on the clock that decides that a mouse is going to die in two years and bowhead whales die in two hundred. If we get to that core thing, then we can keep improving it, and, if you keep reversing, there is a chance that you can do that for a very long time. But I don't think this should be the goal. It's hard to do clinical trials on that. The trial where you show that you've extended life by even fifty years would be a very expensive, very long clinical trial. So, let's just focus on things we can do in weeks.

Link: https://www.lifespan.io/news/george-church-on-gene-therapies-and-longevity/

Cells become senescent in response to potentially cancer-inducing stresses and damage, to tissue injury, or when they reach the Hayflick limit on cellular replication. Senescent cells cease to replicate and secrete pro-inflammatory, pro-growth signals. They are cleared by the immune system or via programmed cell death mechanisms. Their presence is beneficial in the short term, an important part of the panoply of mechanisms devoted to, separately, cancer suppression and regeneration. When senescent cells begin to linger, however, their secretions become highly disruptive to normal tissue function. Senescent cell accumulation is an important contributing cause of chronic inflammation, fibrosis, and other forms of age-related disease. Clearing these cells via senolytic treatments produces rapid and sizable rejuvenation in aged animal models.

Cellular senescence in T cells of the adaptive immune system is a fascinating topic, as immune cells come under a very different pattern of replication stress than is the case for the cells types that make up the tissues of the body. Bursts of replication occur as a part of the immune response to pathogens, damage, and so forth. In the case of persistent pathogens this can lead to an ever increasing burden of replication, pushing ever more T cells to the Hayflick limit and senescence, making the immune system both weaker and actively harmful to the individual. Senescent T cells present in the body for the long term are just as problematic, due to their pro-inflammatory secretions, as lingering senescent cells of other cell types. That has implications for many aspects of health, aging, and age-related disease, cancer included.

Senescent T cells: a potential biomarker and target for cancer therapy

The exhaustion and senescence of T cells are two dominant dysfunctional states in chronic infections and cancers. The principle features of exhausted T cells is the elevated inhibitory receptors, including PD-1, Tim-3, and LAG-3 with impaired cytotoxicity and effector cytokine production. Senescent T cells have a distinct phenotypes including downregulated expression of the costimulatory molecules CD27 and CD28, and high expression of CD57, KLRG-1, and CD45RA. They share common features with senescent somatic cells such as DNA damage, declines in proliferation and activation, but are able to produce high amounts of proinflammatory cytokines. The dysfunction of exhausted T cells can be reversed by immune checkpoint blockades whereas senescent seems to be irreversible. The exhausted and senescent T cells share overlapping characteristics but they are two distinct dysfunctional states.

The accumulation of senescent T cells was first found in the peripheral blood of elderly people. Therefore, T cell senescence is thought to be attributed to the failing efficacy of vaccination and the increased morbidity and mortality from infections and cancer in ageing. Soon thereafter, an increase in senescent T cells was also detected in young patients with chronic viral infections or autoimmune disorders. This phenomenon indicates that in addition to ageing, repeated antigenic stimulation and a chronic inflammatory environment can also lead to T cell senescence. Considering that T cells may be constitutively activated by antigens and influenced by numerous inflammatory cytokines, the tumour microenvironment may be the origin of senescent T cells.

Increasing evidence suggests a link between T cell senescence and tumour progression. Studies have indicated that the tumour microenvironment promotes the senescence of T cells through multiple pathways. The accumulation of senescent T cells may be responsible for advanced cancer and the low response rate to chemotherapy and radiotherapy, as well as immunotherapy. Thus, preventing and restoring T cell senescence could be novel therapeutic strategies for cancer treatment.

Sarcopenia is the name given to the advanced stage of loss of muscle mass and strength, a phenomenon that occurs universally with age, but more rapidly in some people than in others. It is certainly the case that lack of exercise and fitness in later life is problematic, and the cause of a sizable fraction of the problem. Nonetheless, there are mechanisms of degeneration that exercise can only slow, and which will lead to frailty in the end, given enough time alive.

Many potential causes of sarcopenia have a decent amount of supporting evidence. Those that look the most compelling at the present time are defects in the processing of dietary leucine, age-related stem cell dysfunction, the disruption to tissue maintenance caused by chronic inflammation, and molecular damage in the neuromuscular junctions linking the nervous system to muscles. That latter line item is the favored explanation in this open access paper.

We here review the loss of muscle function and mass (sarcopenia) in the framework of human healthspan and lifespan, and mechanisms involved in aging. The rapidly changing composition of the human population will impact the incidence and the prevalence of aging-induced disorders such as sarcopenia and, henceforth, efforts to narrow the gap between healthspan and lifespan should have top priority.

There are substantial knowledge gaps in our understanding of aging. Heritability is estimated to account for only 25% of lifespan length. However, as we push the expected lifespan at birth toward those that we consider long-lived, the genetics of aging may become increasingly important. Linkage studies of genetic polymorphisms to both the susceptibility and aggressiveness of sarcopenia are still missing. Such information is needed to shed light on the large variability in clinical outcomes between individuals and why some respond to interventions while others do not.

We here make a case for the concept that sarcopenia has a neurogenic origin and that in manifest sarcopenia, nerve and myofibers enter into a vicious cycle that will escalate the disease progression. We point to gaps in knowledge, for example the crosstalk between the motor axon, terminal Schwann cell, and myofiber in the denervation processes that leads to a loss of motor units and muscle weakness. Further, we argue that the operational definition of sarcopenia should be complemented with dynamic metrics that, along with validated biomarkers, may facilitate early preclinical diagnosis of individuals vulnerable to develop advanced sarcopenia.

Link: https://doi.org/10.3389/fgene.2021.688526

Much of the signaling that takes place between cells is carried in extracellular vesicles, membrane-wrapped packages of various molecules that are released and taken up by cells. Of late, it has become apparent that mitochondria or mitochondrial component parts can also be released by cells. This is primarily understood as a pro-inflammatory signal resulting from the presence of stressed, damaged, or dying cells. The other functions that this might serve are not completely clear, but researchers have observed that, as is the case for other forms of cell signaling, the presence of mitochondrial DNA in extracellular vesicles changes with age. It remains to be seen as to what can be done with this information.

Many factors contribute to chronic inflammation in the elderly. Cellular damage or stress can initiate a release of mitochondrial damage-associated molecular patterns (DAMPs). As part of this process, mitochondrial DNA (mtDNA) can be released into the extracellular space as circulating cell-free mitochondria DNA (ccf-mtDNA). Due to the similarities between mtDNA and bacterial DNA, this release can in turn elicit a sterile inflammatory response through activation of the innate immune system.

Recent attention has focused on detection and characterization of ccf-mtDNA in the blood. In general, higher plasma/serum levels of ccf-mtDNA have been reported in inflammatory-related diseases, and in response to acute tissue injury such as trauma, acute myocardial infarction, or sepsis. The relationship between ccf-mtDNA and aging is more complex as one report showed an initial decline in ccf-mtDNA into middle-age and then a gradual increase after the fifth decade of life. Individuals greater than 90 years of age with high levels of ccf-mtDNA had higher levels of the proinflammatory cytokines.

Little is known about whether mtDNA is present in plasma extracellular vesicles (EVs) under normal physiological conditions or whether mitochondrial components are important functional cargo in EVs. To address this need, we isolated plasma EVs and analyzed mtDNA levels with human age. Individuals in this aging cohort had donated plasma at two different time points approximately 5 years apart, which enabled us to examine both cross-sectional and longitudinal changes. In both our cross-sectional and longitudinal analyses, EV mtDNA levels decreased with advancing age.

Mitochondrial dysfunction contributes to the aging process. A few recent studies have examined whether mitochondrial components may be functional cargo in EVs. These studies point to a potential mechanism whereby mtDNA in EVs can be transferred to recipient cells and elicit functional changes. However, it is not fully understood whether this is a general mechanism or specific to certain cell types or stimuli. Nevertheless, these initial studies highlight the potential importance of mtDNA in EVs. To further address this, we examined whether EVs from young and old individuals with different mtDNA levels affect mitochondrial function. Cells treated with EVs from old individuals, which contain lower mtDNA levels, had significantly lower basal and maximal respiration than cells treated with EVs from young individuals. These data suggest that EVs from old individuals may impair mitochondrial function.

Link: https://doi.org/10.18632/aging.203358

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