Fight Aging!

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/

Contents

• Amyloidosis Contributes to Muscle Aging, and NAD+ Upregulation Reduces Amyloid Burden
• Cellvie Seed Funded to Develop Mitochondrial Transplantation as a Therapy
• Debating the Connection Between Herpesvirus Infection and Alzheimer's Disease
• A New Era in Research into Aging, Focused on Intervention and Treatment
• The Practice of Calorie Restriction Reduces Blood Pressure and Cardiovascular Risk
• Evidence for Microglia to be Involved in the Depression Accompanying Neurodegenerative Conditions
• Towards a Universal Epigenetic Clock for Mammals
• Longevity Gene INDY is Involved in Blood Pressure Control
• MOTS-c Upregulation Mimics Exercise to Improve Health and Extend Life in Mice
• Further Investigations of Partial, Transient Cellular Reprogramming
• An Example of Automating Nematode Lifespan Studies
• Notes on European Longevity Industry Startups
• A Growing Interest in the Treatment of Aging as a Medical Condition
• Theorizing that Too Much Propionate Contributes to Alzheimer's Disease
• Accelerated Inflammatory Aging Observed in Alzheimer's Disease Patients

Amyloidosis Contributes to Muscle Aging, and NAD+ Upregulation Reduces Amyloid Burden
https://www.fightaging.org/archives/2021/02/amyloidosis-contributes-to-muscle-aging-and-nad-upregulation-reduces-amyloid-burden/

Amyloids are misfolded proteins that can cause other molecules of the same protein to misfold in the same way, linking together into solid deposits that are disruptive to normal cell and tissue function. There are only a score or so of different types of amyloid in the human body, and most are conclusively linked to at least one age-related condition. In today's open access research materials, the scientists involved report on the involvement of amyloid-β (and potentially other amyloids) in muscle aging, connecting loss of mitochondrial function with the growing presence of amyloids.

In order to test the direction of causation in this relationship, the researchers first boosted mitochondrial function in old animals by increasing NAD+ levels. NAD+ is essential to mitochondrial function, but declines with age for a variety of reasons. The proximate causes are fairly well mapped, meaning a loss of efficiency in NAD synthesis and NAD recycling pathways, but connections to the underlying causes of aging remain to be discovered. In this study, improved mitochondrial function reduced the burden of amyloid in muscle tissue. Separately, the researchers also removed amyloid from tissues in a targeted way, and found that this improved mitochondrial function. Thus the relationship appears bidirectional. Amyloid degrades mitochondrial function, while forcing an improvement in mitochondrial function gives cells a greater ability to clear amyloid.

NAD+ can restore age-related muscle deterioration

The older we grow, the weaker our muscles get, riddling old age with frailty and physical disability. Researchers have now looked at the issue through a different angle: the similarities between muscle aging and degenerative muscle diseases. In the study, the scientists identify amyloid-like protein aggregates in aged muscles from different species, from the nematode C. elegans all the way to humans. In addition, they also found that these aggregates also impair mitochondrial function. Although aggregated proteins have been suggested to contribute to brain aging, this is the first time that they have been shown to contribute to muscle aging and to directly damage mitochondria.

But can the formation of the protein aggregates be reversed? To answer this, the researchers fed worms the vitamin nicotinamide riboside and the antitumor agent Olaparib, both of which boost the levels of nicotinamide adenine dinucleotide (NAD+), a biomolecule that is essential for maintaining mitochondrial function, and whose levels decline during aging. In the worms, the two compounds turned on the defense systems of the mitochondria, even when provided at advanced age. Turning on the so-called "mitochondrial quality control system" of mitophagy reduced the age-related amyloid protein aggregates and improved the worms' fitness and lifespan.

The scientists then moved on to human muscle tissue taken from aged subjects. Turning on the same mitochondrial quality control systems produced similar improvements in protein and mitochondrial homeostasis. The encouraging results led the researchers to test nicotinamide riboside in aged mice. The treatment also activated the mitochondrial defense systems and reduced the number and size of amyloid aggregates in different skeletal muscle tissues.

NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle

Due to the fact that mitochondrial function and proteostasis are essential to ensure cellular homeostasis, are functionally interconnected, and decline in aging, it is not surprising that mitochondrial dysfunction and abnormal proteostasis are involved in chronic age-associated neuromuscular proteinopathies, such as Alzheimer's disease (AD), and inclusion body myositis (IBM), a debilitating age-associated muscle disease. Although affecting different organs, AD and IBM are both protein aggregation diseases characterized by the accumulation of amyloid protein deposits. IBM is the most common muscle proteinopathy affecting the elderly; however, it is generally considered a rare disorder, with its overall prevalence still under debate. Skeletal muscle decay instead is one of the most prominent features of aging, characterized by loss of muscle mass and function and by a decline in mitochondrial function. In addition, muscle aging is also typified by dysfunctional proteostasis pathways, including altered ubiquitin-proteasome system (UPS) activity and defective autophagy. Currently, the mechanism underlying the collapse of proteostasis in the aging muscle is not fully elucidated, and it is furthermore unclear whether amyloid deposition, a hallmark of IBM, is also at play in the aging muscle.

Here, we report that, during natural aging, muscle tissues accumulate amyloid-like deposits, a process which is evolutionary conserved in C. elegans, in mouse and human muscle cells and tissues, with molecular features recapitulating some aspects of IBM. Moreover, we also discovered the reversible nature of these deposits, which can be reduced by interventions aimed at restoring mitochondrial homeostasis, such as by enhancing nicotinamide adenine dinucleotide (NAD+) metabolism, even at the onset of aging. Importantly, we show that reduction of the accumulation of amyloid-like deposits in aging is sufficient to improve muscle mitochondrial homeostasis.

Cellvie Seed Funded to Develop Mitochondrial Transplantation as a Therapy
https://www.fightaging.org/archives/2021/02/cellvie-seed-funded-to-develop-mitochondrial-transplantation-as-a-therapy/

Mitochondria are the power plants of the cell, producing chemical energy store molecules to power cellular processes. They are also embedded deeply into may core functions of the cell, from replication to programmed cell death. Mitochondrial function declines throughout the body with age, for reasons that are likely downstream of other more fundamental damage. Mitochondrial dynamics change in ways that make mitochondria more resilient to removal via mitophagy when worn or broken, and mitophagy itself loses efficiency. This may or may not be connected to mitochondrial DNA damage. It is unclear as to whether the progressive accumulation of mutations in mitochondrial DNA has a broad effect on function in most cells, or only results in a small number of highly dysfunctional cells.

Regardless, is it possible to effectively address mitochondrial dysfunction by delivering new mitochondria in large volumes into the body? It is clearly the case that cells ingest whole mitochondria and put them to work when given the opportunity. This option hasn't been aggressively pursued to date by the core rejuvenation biotechnology community, as it seems likely that it could only have a short term benefit. One can argue that functional mitochondrial placed into a dysfunctional environment will soon go the way of their predecessors, and for the same reasons: altered dynamics and diminished mitophagy. Similarly cells overtaken by dramatically broken mitochondria are overtaken because those mitochondria have a replication advantage over their functional peers. In both cases we suspect that transplanted mitochondria wouldn't last in their pristine state.

Now, however, a number of groups are working on practical approaches to mitochondrial transplantation, including today's example, focused initially on applications in medicine in which short term benefits are sufficient. It will be interesting to see how these efforts progress. If it is possible to restore mitochondrial function broadly in the body for at least months, that may prove to be worth the effort in the context of aging. There are other interesting questions to answer along the way, as well. For example, what happens when you replace a large fraction of native mitochondria with mitochondria that contain a different mitochondrial DNA haplogroup? Possibly nothing bad. Perhaps one can swap out any mammal's mitochondrial genome for a better, more efficient, more resilient, artificially augmented mitochondrial genome without any downside - a worthy long-term goal if it is straightforwardly attained. But we just don't know in certainty.

Harvard spin-off Cellvie Inc closes 5M seed round

Cellvie was founded in the US in 2018 and is headquartered close to Zürich, Switzerland. The founders pioneered the approach of mitochondria augmentation and replacement and the team has now set out to leverage the therapeutic potential of mitochondria for a new treatment modality in ischemia-reperfusion injury, aging and beyond. Mitochondria play a crucial role in the aging process, activating factors and metabolic pathways involved in longevity. Their dysfunction impacts on both lifespan and healthspan. "But treating mitochondria has proven to be an arduous challenge. That is why we turned to introducing healthy, viable mitochondria into cells where these organelles are impaired. To great effect. We can sustainably reinvigorate cells' failing energy metabolism."

The potential of therapeutic mitochondrial transfer was recently demonstrated in a clinical investigation at Boston Children's Hospital; paediatric patients on heart-lung-support after suffering a cardiogenic shock received the treatment to revitalise their heart muscle. 80% of these children experienced myocardial recovery, which compares with an expected 29%. "The investment will enable us to pursue the platform broadly, including a first application in aging, where the need for mitochondria-recovery is particularly dear."

To date, Cellvie has focused primarily on ischemia-reperfusion injury (IRI), which manifests itself whenever the blood flow to a part of the body is interrupted and subsequently reintroduced. Well-known medical conditions causing IRI include heart attacks, strokes, and organ transplantation. Cellvie is also pursuing an indication in organ transplantation, for which the FDA awarded orphan drug designation in 2020. The capital injection will be employed for preparing for market, expanding Cellvie's product pipeline and to prepare an IND submission for a clinical study in kidney transplantation.

Debating the Connection Between Herpesvirus Infection and Alzheimer's Disease
https://www.fightaging.org/archives/2021/02/debating-the-connection-between-herpesvirus-infection-and-alzheimers-disease/

The role of persistent infection in the development of Alzheimer's disease is much debated these days, particularly now that the amyloid cascade hypothesis is under attack, following the continued failure of trials for therapies that clear amyloid-β. The biggest challenge in understanding Alzheimer's disease is the question of why only some people develop the condition, even given very similar lifestyle choices relating to weight, exercise, and other well-known influences on health. If the burden of persistent infection is an important contributing factor, it would very conveniently explain this otherwise puzzling outcome.

Herpesviruses and other persistent pathogens are hypothesized to contribute to the development of Alzheimer's via (a) greater chronic inflammation, and (b) greater generation of amyloid-β in its role as a part of the innate immune system response. The mechanisms make sense, but the data for herpesviruses in particular is contradictory, indicating that while herpesvirus infection may contribute to Alzheimer's disease, it likely isn't the major cause. Perhaps other persistent infections are also important. Or perhaps Alzheimer's is in fact a collection of distinct conditions with quite different roots that converge on the same situation of amyloid-β and inflammation in the brain.

New Data Questions Herpes-Alzheimer's Connection

The virus-Alzheimer's tug of war continues. New data across several studies weaken the proposed, and much-debated, association; its proponents are holding fast. A new epidemiology study reports a weak link between herpes and dementia. Researchers combed through four European population-wide healthcare databases and describe equivocal data. In Denmark and Wales, short-term antiviral drug use came with slightly fewer future dementia cases. Alas, in Germany and Scotland, this association did not hold. The opposite was also true; infected people who were not prescribed an antiviral had a slightly higher risk of dementia - but only in the German cohort. "The results are not very encouraging. Some of these associations held no matter what type of dementia or virus was considered. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification."

Twenty-five years ago, researchers linked herpes simplex virus type 1 (HSV-1) infection with an increased risk of Alzheimer's disease (AD). She later spotted the virus hiding in amyloid plaques in brain tissue, and postulated that it may trigger the deposits. Since then, other connections have emerged. Scientists linked viral DNA in the brain to expression changes of genes involved in amyloid metabolism; others proposed that amyloid acts as an antimicrobial peptide.

Still, compelling evidence that viruses, particularly herpesviruses, cause AD remains elusive, although some researchers believe that the teeny irritants could speed disease along. The debate has taken on a new sense of urgency since reports that COVID-19 causes long-term neurological symptoms in a fraction of people who contract the disease. Scientists are just beginning to study this aspect of the infection. "Heterogeneous results are not terribly surprising given the complex nature of AD etiology and pathogenesis, which, so far, does not exclude an infectious component."

A New Era in Research into Aging, Focused on Intervention and Treatment
https://www.fightaging.org/archives/2021/02/a-new-era-in-research-into-aging-focused-on-intervention-and-treatment/

Past research into aging was characterized by a driving philosophy of "look but don't touch". Intervention in the aging process was presented as exclusively the domain of fraud, lies, and marketing, exemplified by the activities of anti-aging marketplace, all hope and non-functional potions. To treat aging was an aspiration that every scientist was strongly encouraged to avoid by those who controlled the research agenda and its funding. This was the case from at least the 1970s until comparatively recently. Only in the past decade or so has the scientific community come around to accept the treatment of aging as a possible, plausible, desirable goal.

That change in attitude was sweeping and comprehensive. Now there is an increased level of funding for the study of mechanisms of aging, and the primary arguments held in public are are over how best to achieve a lengthening of the healthy human life spans. The first rejuvenation therapies have started the lengthy and expensive process of making their way out of the laboratory and into the clinic. Others will follow in the years ahead. These are the early years in an era of rejuvenation, in which the healthy human life span will leap upward as a result of treatments that address the molecular damage that drives aging.

Research: A new era for research into aging

Every major cause of death and disability in the developed world shares a greatest risk factor, and it is probably not what most people would think. Smoking, obesity, a sedentary lifestyle, and drinking too much alcohol all contribute to disease: however, their contributions are small in comparison to the physiological changes that result from aging. Whether biological aging causes the many functional declines that occur with age, or just permits them, is perhaps open for debate, but there is no question that, for most of us, biological aging determines how and when we and our loved ones will get sick and die.

This connection between aging and disease has become particularly consequential during the COVID-19 pandemic, with the vast majority of severe cases and deaths occurring among the elderly. Given this obvious relationship, it is somewhat surprising how slowly the biomedical research community has come to appreciate the importance of biological aging in many of the disease processes under study.

Today, unfortunately, too many scientists study individual diseases without recognizing the impact of aging biology. It is still common, for example, to see research studies in cancer, neuroscience, metabolism, and other fields where young animal models (such as 4-6 month old mice) are used to study disease processes that almost exclusively occur in old people. 'Mice are not people' is a standard refrain when explaining why so many preclinical therapies fail in human trials. Perhaps the mouse isn't the problem. Failing to account for the physiological changes that occur during aging, both in mice and in people, may be a much bigger reason why so much preclinical research fails to translate to the clinic.

Thinking about certain conserved molecular mechanisms as 'hallmarks' or 'pillars' of aging has benefited researchers within the field, and has also allowed scientists outside the field to begin to recognize how aging biology impacts on their own research. Another important advance in aging research has been the development of a concept called geroscience: researchers in this area seek to understand mechanistically how the hallmarks of aging cause age-related disease and functional decline. The growth of the geroscience concept also reflects a recognition that aging research is much closer to clinical application than it was twenty years ago. Numerous interventions have been developed that target one or more of the hallmarks of aging in order to delay, or even reverse, age-related functional declines.

The future of aging research is brighter than ever before, and the pace of discovery is only increasing. We look forward to major breakthroughs over the next few years that will revolutionize the way we think about aging biology and have the potential to significantly impact human healthspan and longevity.

The Practice of Calorie Restriction Reduces Blood Pressure and Cardiovascular Risk
https://www.fightaging.org/archives/2021/02/the-practice-of-calorie-restriction-reduces-blood-pressure-and-cardiovascular-risk/

In today's open access paper, the authors review the evidence for the practice of calorie restriction to reduce blood pressure and cardiovascular disease risk in human subjects. The raised blood pressure of hypertension occurs with age, the result of molecular damage such as cross-linking of blood vessel tissue that impairs elasticity and inflammatory signaling that impairs smooth muscle function. As blood vessels stiffen, the feedback mechanisms governing blood pressure run awry. Lifestyle choices such as lack of exercise and weight gain are also influential on blood pressure.

Hypertension is a major mechanism of aging. It causes increased pressure damage to tissues throughout the body, such as through rupture of small blood vessels, accelerates the progression of atherosclerosis, and pushes cardiac tissue into harmful remodeling that leads to heart failure.

Several human studies of calorie restriction have been conducted since the turn of the century, including those under the CALERIE program. The practice of calorie restriction reliably improves long term health in later life, improving metrics such as blood pressure to a degree comparable to or greater than most drug treatments are capable of achieving. Only with the advent of senolytic treatments to clear senescent cells in aged tissues, and other rejuvenation therapies that will follow, will medical technology begin to provide greater reliable benefits when intervening in the aging process.

Effects of Caloric Restriction Diet on Arterial Hypertension and Endothelial Dysfunction

The calorie restriction diet (CRD) innovative approach consists of a chronic reduction in daily caloric intake of about 25-30% compared to the normal caloric intake, without any exclusion of food groups. Although this regimen is not standardized, numerous studies show its effectiveness. The mechanism of action by which caloric restriction prolongs the life span is not fully understood yet. Recent studies have shown that CRD can determine repair of damaged DNA and decrease fat mass, systolic blood pressure (SBP) and diastolic blood pressure (DBP) values, and the production of free radicals. The results obtained from the CRD can occur quickly, but they can mitigate in case of its suspension.

The CRD would seem to exert a beneficial effect against arterial hypertension (AH) and for this reason represents a useful tool for its clinical management. An important study conducted in this regard was the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy). The CALERIE study was a randomized controlled trial with a two-year follow up. This study was divided in two phases: CALERIE-1 and CALERIE-2. CALERIE-1 study was performed to assess the possible effects induced by a reduction of 10-30% of caloric intake on body composition parameters and lipid profile after 6 and 12 months in a population of middle-aged non-obese subjects. CALERIE-1 results showed an improvement in lipid and glycemic profile and a reduction in body weight (BW) and fat mass.

CALERIE-2 was the largest multi-center study on CRD. A total of 220 subjects were enrolled randomly with a 2:1 allocation into two subgroups: 145 in the CRD group and 75 in the ad libitum group. The CRD group followed 25% caloric restriction for two-years. After two years of diet treatment, cardiometabolic risk factors such as low-density lipoprotein cholesterol (LDL-c), total cholesterol / high-density lipoprotein cholesterol (HDL-c) ratio, SBP and DBP decreased. Moreover, serum biomarkers such as C-reactive protein, insulin sensitivity index and metabolic syndrome score were reduced. Moreover, BW was significantly lower in the CRD group when compared to the ad libitum group (average weight loss in CRD group was 7.5 kg vs average BW increase of 0.1 kg in ad libitum group).

This data showed that a period of two-years of CRD was able to decrease cardiometabolic risk factors in middle-aged non-obese subjects. For this reason, it is possible to consider CRD as nutritional therapeutic approach to enhance life expectancy and reduce the onset of chronic non-communicable diseases such as diabetes mellitus, cancer, chronic kidney disease, and AH, among others.

Other studies have been conducted to investigate the role of CRD in the control of AH. In particular, a study performed on caloric restriction (25%), with two years follow-up, evaluated the possible reduction of CV risk factors and insulin resistance in non-obese subjects and whether the results obtained were maintained over time or were limited to the period study. The authors showed a significant weight loss associated to a decrease in SBP and DBP and an improvement in other parameters, such as lipid profile and insulin resistance. These improvements, with the exception of insulin sensitivity, appeared to be maintained over time.

Evidence for Microglia to be Involved in the Depression Accompanying Neurodegenerative Conditions
https://www.fightaging.org/archives/2021/02/evidence-for-microglia-to-be-involved-in-the-depression-accompanying-neurodegenerative-conditions/

Chronic inflammation and activation of microglia in the brain may contribute to the depression that can accompany neurodegenerative conditions, as well as other diseases that feature persistently raised inflammation. Researchers here provide supporting evidence for that hypothesis. Microglia are innate immune cells of the central nervous system, and increased inflammatory behavior and senescence in this cell population is implicated in age-related neurodegeneration. Clearing senescent microglia can reduce inflammation and reverse tau pathology in animal models of tauopathies, for example.

Research has shown that microglial cells are activated in several neurological diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. People who are affected by these conditions also often fall into a negative mood. Other previous research has suggested that inflammatory processes also play a role in the development of depression. This led the researchers behind the new study to examine more closely whether microglial cells are involved in regulating mood during inflammation. "The study showed that animals feel sick and uneasy when we activate the microglial cells. We demonstrate that two signal molecules, interleukin-6 and prostaglandin E2, are particularly important in these processes. It's not surprising that these signal substances are central, but we were a bit surprised that it is the microglial cells that release these molecules."

During inflammation, many processes are initiated in several cell types. One of the challenges in determining the role played by a specific cell type in the body, therefore, is to isolate its effects. In this study, the scientists used a technique known as chemogenetics, which enabled them to switch on the activity specifically in microglial cells in mice. The researchers activated the microglial cells when the mice were being kept in a certain type of surroundings. The mice subsequently avoided this type of surroundings, which the researchers interpret as showing that the animals disliked the experience. The mice also became less interested in a sweet solution, which they normally find very tempting.

In order to investigate whether the microglial cells are an important link between the immune system and mood, the researchers investigated what happened when microglial cells are inhibited. When the microglial cells were not available for activation, the mice did not feel poorly, even when they had inflammation. This reinforces the idea that these cells are necessary for the process. If further research demonstrates that the biological mechanism described in the study functions in the same way in humans, it may be possible in the long run to reduce symptoms of depression by inhibiting this mechanism.

Towards a Universal Epigenetic Clock for Mammals
https://www.fightaging.org/archives/2021/02/towards-a-universal-epigenetic-clock-for-mammals/

Epigenetic marks are constantly added to and removed from CpG sites on the genome, controlling gene expression and thus cell behavior. The pattern of epigenetic marks in any given cell shifts in response to environment and circumstances, and some of those changes are characteristic of the presence of the underlying molecular damage of aging. Epigenetic clocks can thus be constructed from weighted combinations of epigenetic mark status at various CpG sites in order to measure biological age. Existing epigenetic clocks are specific to a given species, but here researchers process an enormous amount of data from many species to produce epigenetic clocks that are universal to all placental mammals. If this result holds up well in further testing, then such universal clocks could help to speed up the development of therapies that target the mechanisms of aging.

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead underlies the aging process.

To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases.

From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

Longevity Gene INDY is Involved in Blood Pressure Control
https://www.fightaging.org/archives/2021/02/longevity-gene-indy-is-involved-in-blood-pressure-control/

The INDY gene has been known to affect longevity in a range of species for quite some time, as I noted at length back in 2015. It is more than 20 years now since INDY was first discovered to affect fly aging, and work continues to link the outcomes on life span to specific effects on aging and cell function. INDY has effects on metabolism that look a lot like those connected to calorie restriction. A such, it tends to improve every aspect of aging, making it challenging to sort out what is cause, what is consequence, what is important, and what is a side-effect. The research noted here is a representative example of incremental progress in understanding the effects of INDY on aging. I doubt this to be a path that leads to any practical outcome for human health and longevity.

Researchers have presented data showing that the longevity gene mammalian Indy (mINDY) is involved in blood pressure regulation. Reduced expression of mINDY, which is known to extend life span in lower organisms and to prevent from diet induced obesity, fatty liver, and insulin resistance in mice, has now been shown to lower blood pressure and heart rate in rodents.

The authors provided mechanistic insights for the underlying physiological mechanism based on in vivo data in a genetic knock out model as well as microarray and in vitro studies. Furthermore, the hypothesis is supported by confirming critical effects in vitro using a small molecule inhibitor of mINDY. The authors conclude that deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

mIndy deletion attenuates sympathoadrenal support of blood pressure and reduced arterial blood pressure and heart rate in a murine knockout model. Blood pressure was assessed invasively using intra-arterial pressure probes over several days. Urinary analysis for catecholamines and metanephrines as well as unbiased transcriptomic analysis of adrenal glands identified the affected biosynthetic pathways. Indeed, catecholamine biosynthesis was attenuated in mINDY-knockout adrenals, whereas plasma steroids and steroid hormone synthesis were unaffected.

In vitro studies on an adrenal cell line supported this hypothesis. mIndy codes for a carboxylic acid transporter protein expressed in plasma membrane. Citrate, the main substrate of the mINDY transporter, increased catecholamine content, while pharmacological inhibition of mINDY by a small molecule inhibitor blunted the effect.

MOTS-c Upregulation Mimics Exercise to Improve Health and Extend Life in Mice
https://www.fightaging.org/archives/2021/02/mots-c-upregulation-mimics-exercise-to-improve-health-and-extend-life-in-mice/

Upregulation of MOTS-c improves mitochondrial function and has other less well explored influences on stress responses in cells. This might be considered a form of exercise mimetic therapy, given that MOTS-c upregulation is one of the outcomes of exercise. The result of artificial upregulation of MOTS-c in mice is improved health, greater exercise capacity, and extended life span. We should probably not expect life span effects produced by this sort of intervention to translate well to longer-lived mammals, given what we know of the effects of calorie restriction, exercise, and similar interventions that upregulate stress response mechanisms. Benefits to health are certainly plausible, however.

The study looked at the role of MOTS-c, one of several recently identified hormones known to mimic the effects of exercise. However, MOTS-c is unique because it is encoded in the small genome of mitochondria rather than the larger genome in a cell's nucleus. The research team tested how injections of MOTS-c affected mice of different ages by measuring physical capacity and performance in young (2 months), middle-aged (12 months), and old (22 months) mice. When the mice were presented with physical challenges - including maintaining balance on a rotating rod and running on an accelerating treadmill - mice of all ages who had received MOTS-c treatment fared significantly better than untreated mice of the same age.

Even groups of mice that had been fed a high-fat diet showed marked physical improvement after MOTS-c treatment and less weight gain than untreated mice. These findings echo previous research on MOTS-c treatment in mice, which also found that it reversed diet-induced obesity and diet- and age-dependent insulin resistance. Additionally, treating the oldest mice nearing the end of their lives with MOTS-c resulted in marked physical improvements. This late-life treatment improved grip strength, gait (measured by stride length) and physical performance, which was assessed with a walking test (running was not possible at this age)."The older mice were the human equivalent of 65 and above and once treated, they doubled their running capacity on the treadmill. They were even able to outrun their middle-aged, untreated cohorts."

To measure the effects of exercise on MOTS-c levels in people, the researchers collected skeletal muscle tissue and plasma from sedentary, healthy young male volunteers who exercised on a stationary bicycle. Samples were collected before, during and after the exercise as well as following a 4-hour rest. In muscle cells, levels of MOTS-c significantly increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest, while MOTS-c levels in blood plasma also increased by approximately 50% during and after exercise and then returned to baseline after the rest period. The findings suggest that the exercise itself induced the expression of the mitochondrial-encoded regulatory peptides.

Further Investigations of Partial, Transient Cellular Reprogramming
https://www.fightaging.org/archives/2021/02/further-investigations-of-partial-transient-cellular-reprogramming/

Reprogramming cells from old tissues into induced pluripotent stem cells has the effect of reversing many of the epigenetic changes that are characteristic of age, thus restoring mitochondrial function and other aspect of cell behavior. This is a limited rejuvenation: it can't do much about DNA damage, and nor can it make cells clear persistent molecular waste that even youthful cells struggle with. Nonetheless, applying reprogramming to living mice has produced benefits to health, suggesting that if the process can be sufficiently controlled, then it may be a useful basis for therapy - perhaps globally forcing cells to behave more as though they are in young tissues. Groups such as Turn.bio are investigating the use of partial and transient reprogramming, in search of a balance point at which cells are rejuvenated without losing their cell type or radically changing their behavior. Here, another groups reports on early results from their analogous efforts to develop a methodology of safe transient reprogramming.

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells.

Here we have developed the first "maturation phase transient reprogramming" (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method resulted in substantial rejuvenation of multiple cellular attributes, including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent.

The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

An Example of Automating Nematode Lifespan Studies
https://www.fightaging.org/archives/2021/02/an-example-of-automating-nematode-lifespan-studies/

The growth of interest in targeting mechanisms of aging has led to the development of a variety of approaches to automating nematode life span studies, some of which are already available as commercial services. Researchers use the nematode species C. elegans in screening studies, searching for compounds that have effects on life span, or that interact with specific aging mechanisms of interest. Running ten thousand compounds through ten thousand dishes of nematode worms is a daunting prospect if it has to be carried out manually, and automation allows a great deal more screening to be accomplished for a given cost.

Despite being an extremely simple animal, C. elegans has differentiated organs such as nerves, skeletal muscles, and a digestive tract, and many mammalian animal-related genes are conserved. It is very useful for cutting-edge research in fields like genetics and molecular biology. However, while lifespan analysis of this nematode provides a great deal of useful information, previous lifespan studies had many limitations including 1) sensitivity to various stimuli at room temperature, 2) a long experimental time required for daily measurements, 3) a lack of objectivity due to a tendency for results to be dependent on experimental technique, and 4) the small number of samples that can be processed at one time making it unsuitable for simultaneous measurement of many samples.

The researchers attempted to resolve these issues by developing a new healthy lifespan assessment system that maintained the advantages provided by nematodes. They focused on determining the optimal conditions in a live cell imaging system for automatically measuring nematode survival, such as counting the number of nematodes in a sample, incubation temperature, medium thickness, feeding conditions, imaging interval, and survival determination method. This became C. elegans Lifespan Auto-monitoring System (C-LAS), a fully automated lifespan measurement system that can non-invasively measure a large number of samples (currently up to 36 samples). C-LAS uses overlapping images of nematodes to identify those that are moving, meaning they are alive, and those that are not moving, meaning they are dead.

The researchers performed a mini-population analysis of nematode healthy lifespan using a combination of C-HAS and statistical analysis on common nematodes with the same genetic background. They found that about 28% of the population had average lifespans, about 30% had long and healthy lifespans, about 35% had healthy lifespans but died prematurely, and about 7% had a long period of frailty. They also found that activating - either genetically - or through administration of the drug metformin - AMP-activated protein kinase (AMPK), which is closely associated with healthy life expectancy, dramatically increased the population with healthy longevity and reduced the population with long periods of frailty. Metformin is thought to increase healthy life expectancy in humans, and the present study supports this idea. Currently, clinical trials are underway to ascertain its association with healthy longevity.

Notes on European Longevity Industry Startups
https://www.fightaging.org/archives/2021/02/notes-on-european-longevity-industry-startups/

While much of the longevity industry is based in the US, there are a fair number of companies elsewhere in the world, working on approaches that target the mechanisms of aging in order to better treat age-related conditions or improve health in later life. The article here notes some of the European biotech startups in the industry. The main body of commentary on the industry in this article suffers from much the same issues as most popular science coverage of research into the treatment of aging as a medical condition, in that the author makes no attempt to distinguish between parts of the field that cannot possible do much good (near anything involving supplements, definitely anything involving consumer focused digital health) versus parts of the field that have the potential to produce real rejuvenation in the old (such as senolytic drugs).

The Dutch company Cleara Biotech is developing senescence biomarkers for diagnostics and drug targeting. In 2018 it raised a seed round from Apollo Health. Senisca was spun out of Exeter University in 2020 and is dedicated to the development of new approaches to reverse cellular senescence. Senolytic Therapeutics is a Barcelona-based biotech startup founded in 2017 developing novel medicines that target senescent cells. Life Length is a Spanish company founded in 2010 and has developed a technology for measuring telomere length.

Tree Frog Therapeutics is a French stem cell company that develops C-stem, a platform to accelerate the making of self-replicating cells which can form to grow any part of the human body. The UK-US company Juvenescence is creating a network for longevity companies, scientists as well as AI specialists. It has so far invested in approximately 15 startups. The hopes to IPO in the coming year. Eternans is a UK-based biotech startup, founded in 2017, and is developing senolytic agents to selectively kill senescent cells.

Samsara Therapeutics has developed a screening platform that identifies new molecules that extend healthy lifespan across species, and is funded by Apollo Ventures. The Swiss company Rejuveron is a biotech platform company, that together with entrepreneurial scientists, develops and improves therapies and technologies in this space. The UK-US startup Humanity monitors your rate of ageing and helps users understand which actions will slow down the individual's rate of ageing.

Tracked.bio is a Danish biotechnology company that develops fully automated phenotyping and identification systems for model organisms with the use of deep learning. The systems help effectively evaluate the efficacy of ageing interventions. Age Labs is a Norwegian molecular diagnostics company that discovers, develops and commercialises diagnostic tests for the early detection of age-related diseases. The Swiss startup Centaura, founded in 2019, aims to prevent and reverse ageing by using machine learning to analyse the DNA setup in order to develop an ageing profile.

A Growing Interest in the Treatment of Aging as a Medical Condition
https://www.fightaging.org/archives/2021/02/a-growing-interest-in-the-treatment-of-aging-as-a-medical-condition/

There is a growing interest in the treatment of aging as a medical condition, targeting mechanisms that cause aging or that are involved in the pathologies of aging. In the research community this manifests as increased funding, a greater output of potential therapies, more conferences, and more high level reviews of the state of the field, such as the paper noted here. An uptick in reviews in any part of the life siences might be taken as a sign that a field is attracting new participants. On the one hand more researchers want to learn about the state of the science because they are hearing more discussion of the field in their communities, while on the other hand more researchers recently learned enough as a result of participation to consider writing a review for the next set of newcomers.

Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence.

Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.

Theorizing that Too Much Propionate Contributes to Alzheimer's Disease
https://www.fightaging.org/archives/2021/02/theorizing-that-too-much-propionate-contributes-to-alzheimers-disease/

Proprionate is generated by gut microbes, and is generally thought to be beneficial, acting to improve measures of health. Thus it has been lumped in with butyrate and a few other metabolites as beneficial outputs of the gut microbe that decline with age as the microbial populations shift. Researchers here instead discuss the possibility that excessive manufacture of proprionate by the aged gut microbiome can contribute to neurodegeneration. All compounds have a dose response curve, and too much can be just as bad as too little. This commentary on proprionate is an interesting viewpoint: one of the challenges in Alzheimer's research is to explain why only some people exhibit the condition. Perhaps the specific composition and metabolite production of the aged gut microbiome, highly varied between individuals, is an important factor.

The enzymes needed to digest most dietary fibers are lacking in the human body. Therefore, the microbiota in the intestine is tasked with fermenting dietary fibers. Fermentation results in the production of short-chain fatty acids (SCFAs), which serve several important functions. In the gut, they aid in microbial growth. They are also second messengers that can modulate gene expression and initiate the synthesis of gut peptides and hormones.

One of the major SCFAs is propionate. In addition to fermentation, two other sources of propionate are food and the oral microbiome. In 1984, the Food and Drug Administration (FDA) labeled propionate as generally recognized as safe (GRAS) and approved its use for food preservation. Therefore, most persons are exposed to dietary sources of propionate every day. As for the oral microbiome, oral microbiota can produce propionate. Increased propionate levels are associated with gingivitis and periodontal disease.

Propionate serves important roles in the human body. However, our review of the current literature suggests that under certain conditions, excess levels of propionate may play a role in Alzheimer's disease (AD). The cause of the excessive levels of propionate may be related to the Bacteroidetes phylum, which are the primary producers of propionate in the human gut. Studies have shown that the relative abundance of the Bacteroidetes phylum is significantly increased in older adults. Other studies have shown that levels of the Bacteroidetes phylum are increased in persons with AD.

There is evidence for such a wide array of different mechanisms that excess propionate likely leads to AD by way of a combination of multiple different mechanisms. Probably the most well-studied mechanism of propionate induced neurotoxicity is related to its ability to impair the urea cycle, the principal pathway for nitrogen metabolism. This condition, known as hyperammonemia, occurs in propionic acidemia (PA), an autosomal recessive genetic disease characterized by an abnormal accumulation of propionic acid. The clinical manifestations of chronic, slightly elevated blood ammonia levels have received relatively little research interest within the field of dementia research. However, considering the well-known neurotoxic nature of ammonia, it is reasonable to speculate that chronically elevated levels of ammonia might be associated with the development of AD.

Accelerated Inflammatory Aging Observed in Alzheimer's Disease Patients
https://www.fightaging.org/archives/2021/02/accelerated-inflammatory-aging-observed-in-alzheimers-disease-patients/

Alzheimer's disease, like many age-related conditions, has a strong inflammatory component. Short-term inflammation is a necessary part of the immune response to pathogens and injury. When it goes unresolved, however and is sustained for the long term, it is highly disruptive of cell and tissue function. Aged tissues are characterized by damage and the presence of senescent cells, both of which provoke the immune system into a state of constant inflammatory activation. Researchers here analyze data from older individuals to show that while everyone has a progression towards ever greater chronic inflammation, Alzheimer's disease patients are further along in this process than their healthier peers.

In the present study, we measured 73 inflammatory proteins in both cerebrospinal fluid (CSF) and plasma in a large clinical cohort in order to investigate inflammatory pathway changes in Alzheimer's disease (AD). Our finding that both CSF and plasma proteins were highly predictive of age in amyloid-β negative, cognitively unimpaired individuals (Aβ- CU) individuals adds to the established evidence that the innate immune system changes even during healthy aging. From this basis, we showed that the AD continuum is characterized by accelerated biological aging of the innate immune system such that mild cognitive impairment (MCI) and AD patients have inflammatory proteomes which are akin to healthy individuals who are significantly older. This finding is in line with similar biological aging studies of AD carried out using structural brain imaging (i.e. brain age), for example.

Importantly, the abnormal inflammatory aging we observed in the AD continuum is differentially expressed across specific inflammatory pathways and can even differ depending on whether proteins are measured in CSF or plasma. For instance, our results showing that plasma-based inflammatory aging was elevated in AD patients compared to amyloid-β negative (Aβ-) MCI patients suggest that cross-sectional inflammatory levels as measured in plasma may be more AD-specific at a given point in time compared to those measured in CSF. Since CSF-based inflammatory aging correlated strongly with core AD biomarkers and predicted chronological age better than plasma in the main Aβ- CU group, CSF inflammatory proteins likely track more closely with those brain-based inflammatory changes which occur during normal aging.