Fight Aging!

Mitochondria are effectively power plants, hundreds of these organelles per cell working to create the chemical energy store molecule adenosine triphosphate. Mitochondria are the descendants of ancient symbiotic bacteria, and retain many bacterial characteristics, including a small genome, the mitochondrial DNA, and the ability to replicate. Mitochondrial dysfunction is one of the paths by which cells can become senescent, entering a state of growth arrest while secreting an inflammatory set of signals, but mitochondria are in any case involved in the transition to senescence in response to other forms of damage or dysfunction. In youth, senescent cells are quickly destroyed by their own programmed cell death processes or by the immune system. In older people, these cells accumulate, contributing to tissue dysfunction and the chronic inflammation of age.

In today's open access paper, the authors propose treating skin aging by delivering whole mitochondria into senescent cells, thereby rescuing their function. In recent years, various approaches to introducing mitochondria into target cells have been demonstrated. It also appears to be the case that cells naturally transfer, eject, and ingest mitochondria under a range of circumstances. Is rescuing the usual forms of senescent cells found in old tissues a good idea, however? If cellular senescence is largely due to mitochondrial dysfunction, which it may be under some circumstances, then the proposal here isn't completely unreasonable. But cells become senescent for a variety of good reasons, including nuclear DNA damage that is potentially cancerous, and which can occur in skin as the result of exposure to UV radiation. Selectively destroying senescent cells in skin sounds like a safer approach than attempting to rehabilitate them.

For what it is worth, delivering functional and undamaged mitochondria appears best targeted to normal cells in the aging body, to boost their function in an environment of damaged and dysfunctional mitochondria. Indeed, that has been attempted. Mitochondrial function does decline with age in tissues throughout the body. Perhaps something should be done about that. While it is unclear as to whether newly introduced mitochondria would remain functional for long in the aged environment, the strategy sounds worth a try, given the evidence to date for it to enhance tissue function in the short term.

Bases for Treating Skin Aging With Artificial Mitochondrial Transfer/Transplant (AMT/T)

The perception of mitochondria as only the powerhouse of the cell has dramatically changed in the last decade. It is now accepted that in addition to being essential intracellularly, mitochondria can promote cellular repair when transferred from healthy to damaged cells. The artificial mitochondria transfer/transplant (AMT/T) group of techniques emulate this naturally occurring process and have been used to develop therapies to treat a range of diseases including cardiac and neurodegenerative. Mitochondria accumulate damage with time, resulting in cellular senescence. Skin cells and its mitochondria are profoundly affected by ultraviolet radiation and other factors that induce premature and accelerated aging. In this article, we propose the basis to use AMT/T to treat skin aging by transferring healthy mitochondria to senescent cells, possibly revitalizing them.

Mutations related to monogenic mitochondrial disorders can cause fragmentation of the mitochondrial network in the cell. Affecting this network hampers its capacity to maintain mitochondrial DNA (mtDNA) stability. When good and damaged mitochondria are unable to fuse within networks, they can't exchange healthy mtDNA or get rid of damaged DNA copies. This ultimately leads to dysfunctions in the cell and premature senescence. For instance, patients with fibromyalgia suffer from oxidative stress and inflammation of the skin which has been linked to mitochondrial dysfunction. Healthy skin depends on the maintenance of functional mitochondria, which could be a target for the development of medical and cosmetic anti-aging treatments.

To our knowledge, there is no effective treatment available to the public to reverse skin aging by targeting mitochondria. The few existing therapeutic options focused on the mitochondria are under development and still, need further in vitro assays and clinical validation. In addition, no available products, including topical application of natural substances and antioxidants, offer a substantial recovery from many skin aging symptoms such as mtDNA instability, respiration, collagen production, neovascularization, and localized inflammation.

In this hypothesis article we present the idea and arguments of using the artificial mitochondria transfer/transplant (AMT/T) technique as a possible skin anti-aging therapeutic. It has been observed previously that the use of AMT/T in vitro, in vivo, and clinically promotes cell and tissue recovery in different diseases, with effects that could be used to repair skin damage. For example, MitoCeption, one of many AMT/T techniques, induces cell proliferation, migration, and increased respiratory ATP production, processes needed to repair the damage in aged skin. PAMM MitoCeption (Primary Allogeneic Mitochondria Mix Transfer by MitoCeption) repaired UV radiation damaged cells by recovering the loss of metabolic activity, mitochondrial mass, mtDNA sequence stability in addition to decreasing p53 expression. Beyond in vitro applications, AMT/T showed to have regenerative effects in vivo, in diseases such as heart and brain ischemia. AMT/T applied clinically to pediatric patients with myocardial dysfunction has also shown positive results on ischemic injured tissues.

Our hypothesis regarding AMT/T as an antiaging skin therapeutic could be tested in vitro, in vivo, and clinically, to promote the applications of this technique. The possibility to transfer new mitochondria to senescent or age-induced harmed cells in the skin could represent a plausible option to treat the effects of aging.

Researchers here suggest that some of the detrimental effects of prolonged space missions are mediated by an increased burden of senescent cells resulting from cosmic radiation exposure. Senescent cell accumulation is a feature of aging and cancer treatments such as chemotherapy, and contributes to the progression of age-related dysfunction and disease. Senescent cells secrete an inflammatory mix of signal molecules that disrupt nearby tissue structure, alter cell behavior, and rouse the immune system into a state of chronic inflammation. Even a small number of senescent cells can have outsized effects on tissue function due to this signaling.

The increasing duration of space missions involves a progressively higher exposure of astronauts to cosmic rays, whose most hazardous component is made up of High-Atomic number and High-Energy (HZE) ions. HZE ions interact along their tracks with biological molecules inducing changes on living material qualitatively different from that observed after irradiation for therapeutic purposes or following nuclear accidents. HZE ions trigger in cells different responses initialized by DNA damage and mitochondria dysregulation, which cause a prolonged state of sterile inflammation in the tissues. These cellular phenomena may explain why spending time in space was found to cause the onset of a series of diseases normally related to aging.

Despite their concentration in the cosmic rays being around 1%, HZE ions due to their high penetration and strong oxidizing power have been proven to induce permanent damage. The direct or indirect damage through radiolysis of mitochondria has as a consequence not only failure of its metabolic role but also establishment of a persistent oxidative imbalance. Once damaged, mitochondrial DNA may insert in nuclear chromosomes perpetuating genomic instability. The cells bearing DNA damage that cannot be quickly repaired with the DNA damage response system enter into apoptosis or the quiescent state typical of senescence. The final result is a decrease in the tissue functionality as is occurring in aging. Therefore, cosmic rays would mimic the effect of aging, inducing a persistent state of sterile inflammation damaging DNA, proteins, and lipids the consequences of which are aging-related disease such as cardiovascular diseases, neurocognitive impairment, and increase of cancer occurrence.

Link: https://doi.org/10.3389/fphys.2020.00955

Microglia are innate immune cells of the brain, responsible not just for destroying pathogens and errant cells, but also for clearing debris and assisting neurons in managing the connections of neural circuits. With age, microglia become ever more inflammatory and dysfunctional. This is most likely a reaction to the accumulating damage of aging brain tissue, but in addition a significant number of microglia become senescent. Senescent cells are now well known to be harmful if not quickly destroyed by their own programmed cell death processes or by other immune cells; they secrete a potent inflammatory mix of signals that degrade tissue function when present for an extended period of time. Targeted clearance of senescent microglia has been shown to reduce chronic inflammation in brain tissue and reverse processes of neurodegeneration in animal models. It is plausible that addressing the excessive inflammatory activation of non-senescence microglia may be similarly beneficial, if a suitable approach can be found.

Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying the brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate the ongoing neuroinflammation.

A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to the conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) and granulin (GRN) are associated with various neurodegenerative diseases, and these genes are dysregulated in the majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release.

Here we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.

Link: https://doi.org/10.3389/fncel.2020.00246

There are twenty or so different proteins in the body that can become altered in ways that cause them to aggregate into solid deposits known as amyloids, spreading and encouraging other molecules of the same protein to do likewise. Amyloids are a phenomenon of old individuals and old tissues, for reasons that are much debated and no doubt quite complex.

Some of these amyloids are well studied and well known to be harmful, such as the amyloid-β involved in Alzheimer's disease. Others are known but less well studied, and whether or not they are harmful is a question mark. The progression of knowledge over the past decade regarding the damage done by transthyretin amyloid, with new associations with disease states emerging every few years, suggests that looking more closely at any amyloid will turn up ways in which it contributes to age-related tissue dysfunction and disease. The SENS proposals for rejuvenation therapies suggest that all amyloids should be targeted for removal by approaches such as catabodies, firstly on the basis that they are a feature of aging, a distinguishing difference between young and old tissues, and secondly that the amyloids that have been carefully investigated all turned out to be harmful.

Today's research materials are an example of looking more closely at the biochemistry of one specific amyloid, and as a result finding out that it isn't innocuous. Medin is the most common human amyloid, which makes it interesting that there has been just about as little investigation of its role in age-related disease as was the case for transthyretin amyloid until quite recently. Researchers have published evidence for medin to be involved in aortic anyeurism and of late vascular dysfunction in the brain. That latter finding is echoed in the research noted below.

Lumpy proteins stiffen blood vessels of the brain

Nearly all people over the age of 50 are known to have tiny lumps of the protein Medin in the walls of their blood vessels. "These deposits are apparently a side effect of the aging process. They are predominantly found in the aorta and in blood vessels of the upper body, including those of the brain. Most surprisingly, in our study we could not only detect Medin particles in brain tissue samples from deceased individuals but also in old mice - despite the limited lifespan of these animals. It has been assumed for quite some time that Medin aggregates have an unfavorable effect on blood vessels and can contribute to vascular diseases. Recent studies support this hypothesis. According to these previous findings, older adults with vascular dementia show increased amounts of Medin deposits compared to healthy individuals."

However, despite these suspicious signs, there has not yet been conclusive evidence that the protein lumps are actually harmful. A research team has now succeeded in proving this - enabled by their finding that Medin deposits also form in aging mice. In mice, when the brain is active and a higher blood supply is needed, blood vessels with Medin deposits expand more slowly than those without Medin. However, the ability of the vessels to expand rapidly is important for regulating blood flow and providing the brain with an optimal supply of oxygen and nutrients. If this ability is impaired, it can have far-reaching consequences for the functioning of organs. Medin deposits therefore seem to contribute to the deterioration of blood vessel function at an advanced age, and this is probably not only the case in the brain, because the deposits also occur in other blood vessels and could therefore lead not only to vascular dementia but also to cardiovascular disease.

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

Vascular dysfunction, as it develops either during normal aging or vascular disease, remains a major medical problem. The amyloid Medin, which is derived from its precursor protein MFG-E8 (through unknown mechanisms), forms insoluble aggregates in the vasculature of virtually anybody over 50 years of age, and it has been hypothesized that Medin aggregation could contribute to age-associated vascular decline; however, mechanistic analyses have so far been lacking. Our data now demonstrate that reminiscent of humans, mice also develop Medin deposits in an age-dependent manner. Importantly, mice that genetically lack Medin show reduced vascular dysfunction in the aged brain. Therefore, the prevention of Medin accumulation should be investigated as a novel therapeutic approach to preserve vascular health in the aging population.

Chronic inflammation is a feature of aging; the immune system is persistently overactive, and this disrupts tissue function in numerous ways, contributing to the progression of age-related disease. There are still anti-inflammatory mechanisms operating in old people, but these mechanisms are washed out by excessive pro-inflammatory signaling, the response to an age-damaged environment. Scientists here identify one such anti-inflammatory mechanism, an increased presence of microRNA-192 (miR-192) in the extracellular vesicles that pass between cells. Research of this nature may offer a basis for interventions that dial back age-related inflammation with fewer side-effects, in this case via upregulation of miR-192, an important goal in the treatment of aging.

A hyperinflammatory state has been observed in elderly humans and animals, wherein levels of IL-6 and several other pro-inflammatory cytokines in the blood are elevated. Inflammation itself is a necessary part of immune cell-mediated host protection, with pro-inflammatory cytokines mainly produced by innate immune cells, including macrophages, which are essential components for counteracting viral infections before the development of acquired immunity. However, the onset and termination of inflammatory responses must be tightly regulated because excessive inflammation or unbalanced production of inflammatory cytokines and chemokines can be detrimental to the organism.

Recent studies have revealed that small extracellular vesicles (EVs) mediate intercellular communications and influence our immune system. Aging and senescence have been found to modulate EV function, but it remains unclear whether aging affects EV-mediated immune regulation. EVs consisting of 30- to 150-nm lipid bilayer vesicles are the potent systemically circulating factors that regulate immune responses, including inflammation. These vesicles are secreted by many types of cells throughout the body for local or remote cell-to-cell communication, and they contain functional proteins and RNAs, such as microRNAs (miRNAs), which modulate cellular responses. Recent studies have shown that EVs deliver several immune regulatory miRNAs suited to different tasks.

This study found that the microRNA-192 (miR-192) is an aging-associated immune regulatory microRNA whose concentration was significantly increased in aged EVs due to the hyperinflammatory state of aged mice. Interestingly, EV miR-192 exhibited anti-inflammatory effects on macrophages. In our aged mouse model, aging was associated with prolonged inflammation in the lung upon stimulation with inactivated influenza whole virus particles (WVP), whereas EV miR-192 alleviated the prolonged inflammation associated with aging. The hyperinflammatory state of aged mice resulted in reduced production of specific antibodies and efficacy of vaccination with WVP; however, EV miR-192 attenuated this hyperinflammatory state and improved vaccination efficacy in aged mice. Our data indicate that aged EVs constitute a negative feedback loop that alleviates aging-associated immune dysfunction.

Link: https://doi.org/10.1016/j.isci.2020.101520

With the advent of epigenetic clocks that appear able to measure biological age, researchers are interested in putting these clocks to work on the assessment of interventions that might affect the pace and state of aging. It is the case, of course, that today there are all too few interventions that can reliably affect the pace and state of aging. But, arguably, the research community shouldn't let that get in the way of generating data with the interventions that do exist, such as exercise, calorie restriction, or senolytics, even though the effects on longevity in humans are either small or unknown.

The most important challenge in the use of epigenetic clocks is that it remains somewhat unclear as to what exactly it is that these clocks are measuring. In other words which of the underlying mechanisms of aging contribute to the observed epigenetic changes that are characteristic of aging, and the relative size of their contributions. Some researchers, on the other hand, and as is the case here, think that epigenetic changes are an underlying cause of aging, and that puts a different spin on assessing these changes. To some extent the motivation doesn't matter in this case: gathering more data, and particularly data on combinations of interventions, may be a decent first step towards making better use of epigenetic age assessments.

Josh Mitteldorf's latest initiative, The Data-BETA Project, is a bold attempt to learn how a wide range of supplements, dietary changes, and exercise regimes are actually impacting our biological age. "Up until a few years ago, we really only had animal studies to go on for life extension. And then it was a major revolution when Horvath came out with his first methylation clock. The second generation of that clock called the PhenoAge clock came out two years ago and that is what inspired me to think about this study. The crucial point is that the methylation profile derived from PhenoAge is an even better predictor of when you're going to die than PhenoAge itself. So, and this is a theme that I've been putting out there, that's a deep indication that methylation is a driver of aging, and potentially a deeper cause of aging than things like autoimmunity, inflammation, blood pressure, blood sugar, and so on."

As a result, Mitteldorf believes that time is now right to start using methylation clocks to start evaluating anti-aging programs to see what works - and what doesn't. This belief led him to the creation of the Data-BETA Project - a proposed 5,000 person study that will use methylation clocks to measure the anti-aging impact of a wide range of interventions. Importantly, the study will also explore the potential impact of combinations of interventions to produce a bigger anti-aging benefit than the sum of their separate effects. "People have been caught up in this model of studying one intervention at a time, but I think biology doesn't work that way. Biology really is much more holistic than that. We should be looking at combinations of treatments and not expect that there's going to be a single chemical and that's going to solve aging for us. We're much more likely to make progress if we look at combinations of treatments and the interactions from the get-go - not just what the treatment does separately."

Link: https://www.longevity.technology/longevity-interventions-find-out-whats-working-and-what-isnt/

I recently collaborated on a review paper covering the history of clinical work on upregulation of nicotinamide adenine dinucleotide (NAD) as an approach to therapy. This is of interest to the aging research community because NAD is important to mitochondrial function. NAD levels diminish with age, alongside a loss of mitochondrial function that is known to contribute to the onset and progression of many age-related conditions. Animal studies and a few clinical trials have indicated that increased NAD levels may improve, for example, cardiovascular function in older individuals, as a result of improved mitochondrial function in important cell populations.

The most common approaches to increasing NAD levels involve compounds derived from vitamin B3 - niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth. These are involved in the mechanisms of NAD synthesis or recovery. In that sense research into NAD upregulation has been taking place for a century or more, somewhat unknowingly, as researchers characterized the use of high doses of vitamin B3 as an intervention. The more modern phase of this work, deliberately targeting NAD with methodologies that move beyond the use of vitamin B3, has less of a history, but it is nonetheless interesting to note just how far back it goes.

It is also interesting to note the ragged and haphazard character of the clinical work on NAD upregulation, taken as a whole over the past few decades. Many approaches and indications have been tested, but few more than once, and few in large study populations. Further, the studies that used exercise as an intervention show effect sizes on NAD levels that are comparable or better than those that used other approaches. That, to me, raises the question of just how much effort is actually worth putting into NAD-based approaches to the treatment of age-related declines.

Clinical Evidence for Targeting NAD Therapeutically

A number of clinical trials have been conducted recently, with more underway, to rigorously assess NAD pharmacology in the context of aging and metabolic and age-related disease. We have conducted a review of the literature in an attempt to determine whether or not the present human evidence for the potential benefits from NAD pharmacology supports an expansion of efforts to assess this approach to age-related conditions. Of the 36 human trials with published results identified in our literature review, 18 reported on oral administration of NAD precursors, such as nicotinamide, nicotinamide mononucleotide, or nicotinamide riboside, while 8 employed oral administration of NAD. The remainder used an eclectic mix of exercise programs, antioxidants, forms of topical, intravenous, or intramuscular administration of NAD, as well as compounds targeting NQO1 activity. Of the 36 trials, 7 assessed only pharmacokinetics, safety, or biomarkers, and 17 reported beneficial outcomes. The remaining 12 reported no benefits to patients.

Our review reveals that the upregulation of NAD has been studied for a wide range of medical conditions, only a few of which are addressed by more than one study. These conditions include acute kidney injury, Alzheimer's disease, chronic fatigue syndrome, dementia, hyperphosphatemia, hypertension, obesity, Parkinson's disease, photoaging of skin, psoriasis, skin cancers, type 1 diabetes mellitus, type 2 diabetes mellitus, and schizophrenia. NAD levels after intervention were measured in only 11 trials, in blood samples or tissues. In all cases, increased NAD was observed, but the size of the effect varied widely. These changes were almost incomparable due to the current lack of standardization, as variance may be due to differences in methodology of measurement, in interventions, or other factors.

The earliest deliberate attempts at NAD pharmacology, as distinct from the extensive study of vitamin B3, involved the delivery of niacin or formulations of NAD in the treatment of schizophrenia, beginning in the 1960s. This intervention was based on a variety of hypotheses linking NAD biochemistry to the neurobiological changes thought to be involved in schizophrenia. More modern hypotheses of NAD-related redox dysfunction in schizophrenia continue to be debated today; mitochondrial dysfunction and oxidative stress are thought to contribute to the pathogenesis of the condition. Available reports refer to positive results in earlier studies, but the authors reported no benefits to patients resulting from their small clinical trials. Beginning in the 1990s, NAD pharmacology was assessed as a basis for the treatment of Parkinson's disease and Alzheimer's disease, efforts that have since expanded to other forms of dementia. To date, the results of clinical trials have been mixed for Parkinson's disease and largely negative for Alzheimer's disease. Further trials are in progress.

NAD upregulation prevents actinic keratosis and improves some measures of photoaging. While the mechanisms of action are not fully understood, NAD is a co-factor for the PARP enzymes that play a key role in DNA repair. Skin is exposed to UV damage, causing frequent DNA breaks. Improving PARP function, and thus improving DNA repair, might protect from precancerous skin lesions and other consequences of photoaging. This mechanism may also influence the skin pathology associated with dysregulated skin cell division in conditions, such as psoriasis.

Only limited data is available for the use of NAD boosters in the treatment of metabolic conditions, such as obesity and metabolic syndrome. While some studies report improvement in lipid profile, exercise capacity, and muscle fiber composition despite a sedentary lifestyle, others show no benefit of supplementation in the prevention of type 1 diabetes, and no improvements in insulin resistance.

Based on the human trials conducted to date, NAD pharmacology is a promising treatment strategy that is likely to be safe for human use. However, despite several decades of active investigation, there is still only suggestive evidence, in the form of a few successful and sufficiently powered clinical trials, for NAD upregulation to be effective for any of the many potential indications where it may benefit patients. More and larger studies are required to produce robust data in support of NAD pharmacology. This includes in particular studies in which different forms of NAD upregulation are compared consistently with one another. For example, exercise programs tailored to older individuals may be more effective than all of the existing approaches to NAD pharmacology. Whether or not this is the case is one of the more important questions for the research community to answer.

The study results here provide an interesting comparison between the strategies of lowering inflammation and lowering blood cholesterol for the treatment of atherosclerosis. Atherosclerosis is the name given to the buildup of fatty lesions in blood vessel walls, a process that occurs in all of us with advancing age. These deposits narrow and weaken blood vessels, ultimately leading to a fatal rupture or blockage. This is one of the largest causes of human mortality. Unfortunately the present dominant approach of reducing blood cholesterol - via statins and similar therapies - doesn't do more than modestly slow the condition, and only slightly diminishes the size of existing lesions. While atherosclerosis appears to have a strong inflammatory component, in that it progresses more rapidly in the presence of greater age-related chronic inflammation, dampening that inflammation doesn't appear to do any better than reducing blood cholesterol when it comes to turning back the condition and reducing lesion size. Different approaches are going to be needed, perhaps along the lines of removing the lipids present in lesions more directly.

Chronic inflammation in people with psoriasis is associated with a higher risk of developing coronary artery disease. Biologic therapy medications are proteins that are given by injection or infusion and suppress the inflammation process by blocking the action of cytokines, which are proteins that promote systemic inflammation. Previous research has shown a clear link between psoriasis and the development of high-risk coronary plaque. This study provides characterization of a lipid-rich necrotic core, a dangerous type of coronary plaque made up of dead cells and cell debris that is prone to rupture. Ruptured plaque can lead to a heart attack or stroke.

The analysis involved 209 middle-aged patients (ages 37-62) with psoriasis who participated in the Psoriasis Atherosclerosis Cardiometabolic Initiative at the National Institutes of Health, an ongoing observational study. Of these participants, 124 received biologic therapy, and 85 were in the control group, treated only with topical creams and light therapy. To measure the effects of biologic therapy on arteries of the heart, the researchers performed cardiac computed tomography (CT) scans on all study participants before they started therapy and one year later. The CT results between the two groups were then compared.

Biologic therapy was associated with an 8% reduction in coronary plaque. In contrast, those in the control group experienced slightly increased coronary plaque progression. Even after adjusting for cardiovascular risk factors and psoriasis severity, patients treated with biologic therapy had reduced coronary plaque. "There is approximately 6-8% reduction in coronary plaque following therapy with statins. Similarly, our treatment with biologic therapy reduced coronary plaque by the same amount after one year. These findings suggest that biologic therapy to treat psoriasis may be just as beneficial as statin therapy on heart arteries."

Link: https://newsroom.heart.org/news/biologic-therapy-for-psoriasis-may-reduce-heart-disease

The fasting mimicking diet emerged from efforts to better define the dose-response curve for beneficial effects resulting from a reduced calorie intake. Fasting is beneficial, calorie restriction is beneficial, but where are the dividing lines? How much food can one eat and still obtain near all of the benefits of fasting? As a result of this work, the fasting mimicking diet has undergone clinical testing in cancer patients. Numerous benefits have been demonstrated, and the paper here is an example of the type. In this human trial, fasting mimicking reduced the negative short term impact of chemotherapy on health, and, further, three to four times as many patients experienced a strongly beneficial response to the chemotherapeutic treatment.

Extensive preclinical evidence suggests that short-term fasting and fasting mimicking diets (FMDs) can protect healthy cells against the perils of a wide variety of stressors, including chemotherapy, simultaneously rendering cancer cells more vulnerable to chemotherapy and other therapies. Essentially, fasting causes a switch in healthy cells from a proliferative state towards a maintenance and repair state. Malignant cells, in contrast, seem to be unable to enter this protective state because of oncoprotein activity, and therefore fail to adapt to nutrient scarce conditions. Instead, fasting deprives proliferating cancer cells of nutrients and growth factors, which renders them more sensitive to cancer therapy and increases cell death. The phenomenon by which normal but not cancer cells become protected to toxins is termed differential stress resistance (DSR) whereas the specific sensitization of cancer cells to stress is called Differential Stress Sensitization (DSS).

Declines of plasma levels of insulin like growth factor-1 (IGF-1), insulin, and glucose are among the mediators of the effects of fasting on cancer cells, as these factors can promote growth and prevent apoptosis. Fasting periods of at least 48 hours are required to induce a robust decrease in circulating glucose, IGF-1, and insulin levels. A very low calorie, low protein FMD was developed for its ability to cause metabolic effects on various starvation response markers similar to those caused by water-only fasting, while reducing the burden associated with a water only fast.

In the DIRECT trial, we randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg/m2, to receive either FMD or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (odds ratio 3.168). Moreover, per-protocol analysis reveals that the 90-100% tumor-cell loss is more likely to occur in patients using the FMD (odds ratio 4.109). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting and FMD in cancer therapy.

Link: https://doi.org/10.1038/s41467-020-16138-3

Today's open access paper discusses the impact of mitochondrial DNA damage on female reproductive capabilities. Mitochondria are the power plants of the cell, a herd of hundreds of organelles responsible for packaging the chemical energy store molecule ATP, used to power cellular processes. They are additionally deeply integrated into many core cellular processes. Mitochondria are the evolved descendants of ancient symbiotic bacteria: they carry their own small genome, the mitochondrial DNA, and replicate like bacteria. Unfortunately this mitochondrial DNA is more vulnerable and less proficiently repaired than the nuclear DNA in the cell nucleus, and it accumulates mutational damage. Most is washed out by cell turnover in the body, but this damage nonetheless adds up over a lifetime.

Some rare forms of mitochondrial DNA mutation, such as large deletions, can give rise to dysfunctional mitochondria that overtake their cells. The cell itself becomes dysfunction, exporting damaging reactive molecules into the surrounding tissue. This happens infrequently, but is sufficiently problematic when it does occur for it to contribute to aging. Other forms of mitochondrial mutation, such as point mutations, can also be a problem via a more subtle degradation of mitochondrial function. Mutator mice that accumulate this form of damage much more rapidly than their peers exhibit accelerated age-related degeneration, however. This is driven by the progressively greater dysfunction of mitochondria throughout the body.

Researchers here note that the dysfunction of mitochondria produced by point mutations in mutator mice causes a disruption in NAD metabolism. NAD in aging and mitochondrial function has been a topic of growing interest for some years now. NAD levels decline with age, but the cycling of NADH to NAD+ and back again is a central portion of the processes by which mitochondria produce ATP. There are a variety of ways in which NAD levels can be increased, primarily compounds vitamin B3 and related compounds: niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth. It is unclear than any of these produce better results than exercise programs when it comes to increasing NAD+ levels, but they can be convenient tools for animal studies. That is the case here, where nicotinamide mononucleotide is used to reverse some of the imbalance in mitochondrial function caused by point mutations, and thus restore some lost ovarian function.

On the whole, it seems surprising that stochastic mitochondrial DNA point mutations could be responsible for meaningful age-related degeneration in humans (the sizeable loss of fertility) by age 40, given that a 40 year old human is still in fairly good physical shape, looking at mortality and disease risk across the board. Why just this ovarian loss of function and not a much larger general decline, if there are point mutations degrading mitochondrial function everywhere? It may be the case that critical ovarian tissue is especially sensitive to this particular mechanism of aging, but more research is needed on that topic.

Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox

Aging is one of the key factors in both male fertility and female fertility. Indeed, female fertility normally peaks at age 24 and diminishes after 30, with pregnancy occurring rarely after 50. Mitochondrial malfunction has been hypothesized to play important roles in age- and environment-induced infertility. For instance, mitochondrial DNA (mtDNA) deletions were reported to accumulate in human ovarian aging. However, the links among aging, mtDNA mutations, and infertility remain not fully understood.

mtDNA-mutator (PolgAMut/Mut) mice are widely used as an experimental model to study the roles of mtDNA mutations in aging process. The PolgAMut/Mut mice harbor a mutation in the nuclear DNA-encoded mitochondrial polymerase PolgA, leading to the inactivation of its proofreading function. As compared to wild-type (WT) mice, the PolgAMut/Mut mice exhibited a ~10-fold higher mtDNA mutation frequency, eventually leading to a progressive decline in the function of mtDNA-encoded respiratory complexes. PolgAMut/Mut mice were reported to show a reduced life span that is limited to 13-15 months. Consistently, aging-associated disorders occurred approximately 6-8 months after the birth of the PolgAMut/Mut mice.

In the present study, we first determined how mtDNA mutations in human female oocytes changed with age. We analyzed oocyte quality of young (≤30 years old) and elder (≥38 years old) female patients and show the elder group had lower blastocyst formation rate and more mtDNA point mutations in oocytes. Using the PolgAMut/Mut mouse model, we demonstrate mtDNA mutations decrease the fertility of females, but not males, via reducing ovarian primordial and mature follicles. We further show that accumulation of mtDNA mutations decreases female fertility by reducing oocyte's NADH/NAD+ ratio and that nicotinamide mononucleotide (NMN) is remarkably capable of ameliorating infertility in female PolgAMut/Mut mice.

Hearing loss is a prevalent problem with age, the result of loss of sensory hair cells of the inner ear, or as seems more likely in recent years, damage to those parts of the peripheral nervous system connecting hair cells to the brain. Chronic inflammation is a noted aspect of aging, excessive activity of the immune system, and is very disruptive to tissue function and maintenance throughout the body. Researchers here provide evidence to suggest that this persistent inflammation in older individuals is an important factor in age-related hearing loss.

Age-related hearing loss (AHL) or presbycusis is a universal sensory disorder in modern society and affects about 25-40% of people over 65 years. The underlying mechanisms of AHL include oxidative stress, mitochondrial DNA mutations, autophagy impairment, and non-coding RNA disorders. However, the mechanism of cochlear degeneration during aging is still not fully understood. In recent years, the effects of inflammation on aging-related disorders have been extensively investigated. During aging, the body suffers from chronic low-grade inflammation, a phenomenon also referred to as "inflammaging". Chronic inflammation is a consequence of immunosenescence, the aging of the immune system, and is primarily characterized by increased levels of proinflammatory cytokines in response to various stressors. However, only little research on the potential role of inflammation in AHL has been reported.

The current study was designed to determine the transcriptional changes of cochlear genes and the most significantly affected functions and pathways during aging in C57BL/6 mice using next generation sequencing. Our RNA-sequencing data revealed that transcripts associated with aging, apoptosis, and necroptosis were significantly modulated in aged cochleae. Importantly, numerous genes related to immune responses and inflammation were differentially expressed during aging. Bioinformatics analysis of the upregulated genes also revealed that a large portion of biological processes and pathways are related to immune and inflammatory pathways, such as complement system and macrophage activation. Whereas, lots of the downregulated genes are involved in biological processes and pathways associated with ion channel function and neuronal signaling. These findings suggest chronic inflammation may be associated with aging-related cochlear degeneration.

Link: https://doi.org/10.7717/peerj.9737

The practice of calorie restriction improves many measures of health, and extends life meaningfully in short lived species such as mice. Unfortunately, while calorie restriction improves health in much the same way in humans, the effects on longevity are much smaller in long-lived species than is the case for short-lived species. Nonetheless, given that it is an intervention that requires no great effort or cost to carry out, it is well worth it for the health benefits that it does provide, such as a reduced risk of suffering age-related conditions, and a postponement of many of the more evident declines of age. One has to be realistic about the modest effects on life span in our species, but it remains interesting to see papers such as the one here, examining just one of the many ways in which calorie restriction is beneficial.

This study aimed to reveal the impact of calorie restriction on the intestine via structural and molecular changes in terms of intestinal stem cell (ISC) function, ISC niche, intestinal epithelial barrier function, and intestinal immune function. Female C57BL/6J mice, aged 12 months, fed a commercial chow were used in this study. The ISC function, ISC niche, intestinal epithelial barrier function, and intestinal immune function were assessed.

Calorie restriction reversed aging-induced intestinal shortening and made the crypts shallower. The intestinal epithelial cells isolated from the intestine showed a significant increase in the expression levels of stem cell-associated genes in small intestinal epithelial cells as detected by flow cytometry. Despite the increase in the number of stem cells and the expression levels of markers, no increase or decrease was found in the enteroid complexity of the small intestine and colonic enteroid formation in vitro.

The colonic mucous layer was measured in mice of the calorie restricted (CR)-treated group to investigate the epithelial barrier function in the colon. The results revealed that the barrier was more complete. The fluorescence intensity of tight junction markers claudin-2 and zonula occludens-1 increased and the mRNA expression profiles of monocyte chemotactic protein 1 and interleukin-6 decreased in the colon of mice in the CR-treated group. The beneficial effects of CR on the colon in terms of the integrity of the mucosal barrier and alleviation of inflammation were confirmed, thus highlighting the importance of modulating the intestinal function in developing effective antiaging dietary interventions.

Link: https://doi.org/10.1016/j.nutres.2020.06.015

Osteoporosis is the name given to the characteristic age-related loss of bone mass and strength. The extracellular matrix of bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. The proximate cause of osteoporosis is a tilt in the balance of these processes, favoring osteoclast activity and thus slow loss of bone structure.

Today's research materials discuss a most intriguing result: in mice, maintaining a higher environmental temperature slows the progression of osteoporosis. Interesting, but is it a path to therapy? As is always the case when looking at metabolic responses to environmental differences in mice, there is the question of whether similar effects in humans are anywhere near as large All too many examples of this sort of thing are, unfortunately, clearly of little interest as a basis for human therapies because larger mammals respond less strongly. Here, however, a range of epidemiological data from hotter versus colder regions of the world suggests that, yes, the effect of temperature on osteoporosis in humans may be large enough to care about.

Perhaps the most interesting part of this work is the investigation into underlying mechanisms. It appears that the effect of temperature on osteoporosis is mediated by differences in the gut microbiome. In hotter climates, there is a greater microbial production of the metabolite polyamine, known to beneficially affect bone tissue maintenance. Transplanting gut microbes from high temperature environment mice to mice with osteoporosis modestly reverses the progression of the condition, improving bone density, but this benefit is not realized in mice in which polyamine production is inhibited.

Stronger bones thanks to heat and microbiota

Many biologists are familiar with Allen's Rule, according to which animals living in warm areas have a larger surface area in relation to their volume than animals living in colder environment. Indeed, a larger skin surface allows better evacuation of body heat. By placing several groups of adult mice in a warm environment, scientists observed that while bone size remained unchanged, bone strength and density were largely improved.

What about human beings? The research team analysed global epidemiological data on the incidence of osteoporosis in relation to the average temperature, latitude, calcium consumption, and vitamin D levels. Interestingly, they found that the higher the temperature, the fewer hip fractures - one of the main consequences of osteoporosis - regardless of other factors.

Scientists wanted to understand the role of the gut microbiome in these metabolic modifications. To this end, they transplanted the microbiota of mice living in a 34°C environment to osteoporotic mice, whose bone quality was rapidly improved. Thanks to the state-of-the-art metagenomic tools developed in their laboratory, the scientists then succeeded in understanding the role played by microbiota. When adapts to heat, it leads to a disruption in the synthesis and degradation of polyamines, molecules that are involved in ageing, and in particular in bone health.

Warmth Prevents Bone Loss Through the Gut Microbiota

Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation.

Combinatorial metagenomics / metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.

Sarcopenia is the name given to the characteristic loss of muscle mass and strength that occurs in later life, the result of numerous contributing processes of damage and decline. Researchers here find that long-term treatment with rapamycin, and thus likely other more targeted approaches to mTORC1 inhibition, slows the onset of sarcopenia in mice by preserving the function of neuromuscular junctions, the links between nerves and muscles. The most important contributing cause of sarcopenia is likely to be a slowdown in muscle stem cell activity. Interestingly, these stem cell populations appear to remain viable, but are increasingly quiescent in response to the damaged and inflammatory environment of aged tissues. This work suggests that damage and declining function of neuromuscular junctions should be given a greater weight than previously considered, however.

Recently, nine processes involved in aging were proposed, namely cellular senescence, stem cell exhaustion, genomic instability, telomere attrition, loss of proteostasis, deregulation of nutrient sensing, epigenetic alterations, mitochondrial dysfunction, and altered intracellular communication. Each biological process fulfils three hallmark criteria: (1) it occurs during normal aging, (2) intensifying the process accelerates aging, and (3) dampening the process delays aging. Overactivity of the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is central to many of these processes, and dampening mTORC1 activity by its allosteric inhibitor rapamycin is one of the most effective interventions to prolong life. However, mTORC1 activity is also required for muscle hypertrophy. Therefore, there is concern that suppressing mTORC1 to extend lifespan could be at the expense of skeletal muscle function, thereby extending the "poor-quality" period of life.

In previous work, we have shown that mTORC1 activity must be finely balanced in skeletal muscle. Here, we demonstrate that long-term rapamycin treatment is overwhelmingly positive in aging skeletal muscle, preserving muscle size, function, and neuromuscular junction (NMJ) integrity. Interestingly, responsiveness to rapamycin differs between muscles, suggesting that the primary drivers of age-related muscle loss may differ between muscles. To dissect the key signaling nodes associated with mTORC1-driven sarcopenia, we create a comprehensive multimuscle gene expression atlas from (1) adult (10-months old), (2) geriatric (30-months old), and (3) geriatric, rapamycin-treated mice using mRNA-seq. Our data point to age-related NMJ instability as a focal point of mTORC1-driven sarcopenia. Maintenance of NMJ structure and transmission efficiency is crucial for preserving muscle function at high age.

Link: https://doi.org/10.1038/s41467-020-18140-1

The geroscience view of the treatment of aging isn't limited to the reuse of existing drugs that happen to upregulate stress responses in ways that modestly slow aging, but this is the near entirely the focus of those researchers who publish on the topic. Unfortunately the effect size of this approach to aging is small, and diminishes as species life span increases. We know the upper limits of what can be achieved with the beneficial stress response induced by calorie restriction in humans, and we know that it won't really add more than a couple of years to human life spans. Better strategies exist, based on the development of biotechnologies that repair the underlying cell and tissue damage that causes aging. Repair can in principle achieve rejuvenation, not just a modest slowing of aging, and that rejuvenation has already been demonstrated in animal models for the repair-based approach of removing senescent cells from old tissues.

In women 35 years and older the incidences of infertility, aneuploidy, and birth defects dramatically increase. These outcomes are a result of age-related declines in both ovarian reserve and oocyte quality. In addition to waning reproductive function, the decline in estrogen secretion at menopause contributes to multi-system aging and the initiation of frailty. Both reproductive and hormonal ovarian function are limited by the primordial follicle pool (PFP), which is established in utero and declines irreversibly until menopause. Because ovarian function is dependent on the PFP, an understanding of the mechanisms that regulate follicular growth and maintenance of the PFP is critical for the development of interventions to prolong the reproductive lifespan.

Manipulating the rate of aging and delaying the onset of aging-related diseases have been the makeup of medical, scientific, and pseudo-scientific pursuits throughout history. However, it is not until relatively recently, in the later part of the 20th and early 21st centuries, that the molecular targets and geroscience approaches needed to make this a reality have been elucidated. For example, improvements in reproductive function after rapamycin treatment are evident in studies of physiologic murine aging. A 2-week course of rapamycin in healthy mice improved primordial follicle count, oocyte morphology, and mitochondrial activity. In mating studies, after 12 months of age, when the control mice began to experience age-related infertility, the rapamycin-treated mice retained fertility and continued to have pups. Equally, a 12-month course of resveratrol in mice increased primordial follicle counts, litter size, and oocyte quality at advanced ages. Additionally, a specific SIRT1 activator SRT1720 administered to mice suppressed the activation of primordial follicles and increased the ovarian reserve by activating SIRT1 and inhibiting mTOR signaling.

Multiple pathways, many of them nutrient-sensing, converge in the mammalian ovary to regulate the quiescence and activation of primordial follicles. The PI3K/PTEN/AKT/FOXO3 and mTOR pathways appear to be central to the regulation of the primordial follicle pool; however, GH/IGF-1 and H2S may also play a role. A delicate balance of primordial follicle activators and suppressors must be maintained in order to allow for continued ovulation while preventing rapid depletion of the ovarian reserve. The behavioral and pharmacologic interventions that prevent primordial follicle activation, including DR and rapamycin, cause infertility for the duration of the intervention. In order for these interventions to be useful clinically, the resulting period of infertility must be reversible, and the treatments must confer long-term benefits after a relatively short duration of use.

Link: https://doi.org/10.1093/gerona/glaa204