Fight Aging! Newsletter, June 22nd 2020

Researchers have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. Additionally, the molecule decreases insulin resistance and has beneficial effects on oxidative stress and inflammation. The findings hold promise for future treatment and prevention of obesity, diabetes, and especially nonalcoholic steatohepatitis (NASH), a type of fatty liver disease that is characterized by inflammation and fat accumulation in the liver.

The mitochondria are commonly referred to as the powerhouses of the cell. The organelle generates ATP, a molecule that serves as the energy currency of the cell, which powers body movement and other biological processes that help our body to function properly. In order to make ATP, nutrients need to be burned and a proton motive force (PMF) needs to be established within the mitochondria. The PMF is generated from a proton gradient, where there is a higher concentration of protons outside of the inner membrane and a lower concentration of protons in the matrix, or the space within the inner membrane. The cell creates ATP whenever protons pass through an enzyme called ATP synthase, which is embedded in the membrane. Hence, nutrient oxidation, or nutrient burning, is coupled to ATP synthesis. Mitochondrial uncouplers transport protons into the matrix by bypassing ATP synthase, which throws off the PMF. To reestablish the gradient, protons must be exported out of the mitochondrial matrix. As a result, the cell begins to burn fuel at higher than necessary levels.

Knowing that these molecules can change a cell's metabolism, researchers wanted to be sure that the drug was reaching its desired targets and that it was, above all, safe. Through a series of mouse studies, the researchers found that BAM15 is neither toxic, even at high doses, nor does it affect the satiety center in the brain, which tells our body if we are hungry or full. Another side effect of previous mitochondrial uncouplers was increased body temperature. Researchers measured the body temperature of mice who were fed BAM15. They found no change in body temperature. In the BAM15 mouse studies, animals ate the same amount as the control group - and they still lost fat mass.

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity.

BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

All people age, but individuals do so at different rates, some faster and others slower. While this observation is common knowledge, there is no universally accepted measure of biological aging. Numerous aging-related metrics have been proposed and tested, but no marker to date has been identified or noninvasive method developed that can accurately measure and track biological aging in individuals. In what is believed to be the first study of its kind, researchers have discovered that a specialized eye scanner that accurately measures spectroscopic signals from proteins in lens of the eye can detect and track biological aging in living humans.

"The lens contains proteins that accumulate aging-related changes throughout life. These lens proteins provide a permanent record of each person's life history of aging. Our eye scanner can decode this record of how a person is aging at the molecular level. Eye scanning technology that probes lens protein affords a rapid, noninvasive, objective technique for direct measurement of molecular aging that can be easily, quickly, and safely implemented at the point of care. Such a metric affords potential for precision medical care across the lifespan."

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo.

We used quasi-elastic light scattering (QLS) to measure age-dependent signals in lenses of healthy human subjects. Age-dependent QLS signal changes detected in vivo recapitulated time-dependent changes in hydrodynamic radius, protein polydispersity, and supramolecular order of human lens proteins during long-term incubation (~1 year) and in response to sustained oxidation (~2.5 months) in vitro. Our findings demonstrate that QLS analysis of human lens proteins provides a practical technique for noninvasive assessment of molecular aging in vivo.

Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice.

This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice.

Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (-60.1% females, -45.6% males), and bone marrow stromal cells (BMSC) derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (-88% females, -83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures.

Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax's potential (or risk) as a therapeutic agent for combating age-related musculoskeletal dysfunction and bone loss.

Due to their postmitotic status, the potential for neurons to undergo senescence has historically received little attention. This lack of attention has extended to some non-postmitotic cells as well. Recently, the study of senescence within the central nervous system (CNS) has begun to emerge as a new etiological framework for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).

The presence of senescent cells is known to be deleterious to non-senescent neighboring cells via development of a senescence-associated secretory phenotype (SASP) which includes the release of inflammatory, oxidative, mitogenic, and matrix-degrading factors. Senescence and the SASP have recently been hailed as an alternative to the amyloid cascade hypothesis and the selective killing of senescence cells by senolytic drugs as a substitute for amyloid beta (Aß) targeting antibodies.

Here we call for caution in rejecting the amyloid cascade hypothesis and to the dismissal of Aß antibody intervention at least in early disease stages, as Aß oligomers (AßO), and cellular senescence may be inextricably linked. We will review literature that portrays AßO as a stressor capable of inducing senescence. We will discuss research on the potential role of secondary senescence, a process by which senescent cells induce senescence in neighboring cells, in disease progression. Once this seed of senescent cells is present, the elimination of senescence-inducing stressors like Aß would likely be ineffective in abrogating the spread of senescence. This has potential implications for when and why AßO clearance may or may not be effective as a therapeutic for AD.

The selective killing of senescent cells by the immune system via immune surveillance naturally curtails the SASP and secondary senescence outside the CNS. Immune privilege restricts the access of peripheral immune cells to the brain parenchyma, making the brain a safe harbor for the spread of senescence and the SASP. However, an increasingly leaky blood brain barrier (BBB) compromises immune privilege in aging AD patients, potentially enabling immune infiltration that could have detrimental consequences in later AD stages. Rather than an alternative etiology, senescence itself may constitute an essential component of the cascade in the amyloid cascade hypothesis.

The heart is an organ with high energy demand: mitochondria content in cardiomyocytes is up to 70%. During aging and stress conditions, the metabolic pattern changes in cardiomyocytes, which is critically involved in the regulation of cardiomyocyte dysfunction and senescence. The non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment also contribute to the (dys)function/senescence of cardiomyocytes. In turn, the senescent cardiomyocytes modulate the microenvironment to contribute to functional compensatory response or decompensatory remodeling and cardiac dysfunction.

Although cell senescence plays essential roles in wound healing, limiting atherosclerotic plaque size, and preventing infections, the effects of cell senescence can be detrimental or beneficial. The exact roles of senescent cells that contribute to aging and age-related diseases can be named "senescaging". Further studies are still needed to explore the physiological and pathological functions of senescent cardiomyocyte during cardiac development, regeneration, and pathological remodeling, and to elucidate how senescaging contributes to cardiac aging and disease. Specifically, more studies are needed to answer whether cardiomyocyte senescence critically contributes to cardiac aging and the related heart failure with preserved ejection fraction (HFpEF).

Microenvironmental non-myocytes function as central regulators of cardiomyocyte senescence, and metabolism switch is important for the homeostasis and senescence of cardiomyocytes. As thus, an interesting point is whether these non-myocytes affect the metabolic pattern of cardiomyocyte undergoing senescence. Also, studies are needed to explore how metabolism alternations in non-myocytes contribute to cardiomyocyte senescence and cardiac aging. Many studies have been carried out to study the effects of non-myocytes on cardiomyocyte senescence. Some studies also explored the paracrine effects of cardiomyocytes on non-myocytes. However, our knowledge about the effects of senescent cardiomyocytes on microenvironmental non-myocytes is few and further efforts are needed.

An interesting question is whether cardiomyocyte senescence and the myocardial microenvironment could serve as targets for anti-aging drugs such as the popular senolytics. Senolytics were recently reported to repress senescence and inhibit cardiac disease such as myocardial infarction and repress age-related vasomotor dysfunction and atherosclerosis. Further studies are still needed to elucidate how senolytics target cardiomyocyte senescence and local microenvironment, and that whether other anti-aging drugs could repress the senescaging of myocardial microenvironment.

Ventriculomegaly is an abnormal condition in which fluid accumulates in the ventricles of the brain without properly draining, making them enlarged. Although ventricular enlargement within normal range is not itself considered a disease, when left unchecked it can lead to ventriculomegaly and dementia resulting from normal pressure hydrocephalus. In their study, the team found that ventriculomegaly was associated with changes in blood circulation of the brain.

After blood circulates through the brain providing necessary oxygen, the deoxygenated blood must return to the heart though our veins. This happens through two pathways, one draining blood from regions close to the surface of the brain, and the other from areas deep in the brain. By using MRI to measure changes in blood flow, the team recently found that as we age, the time it takes for blood to drain through these two pathways becomes out of sync. The result is a time lag between the deep drainage pathway and the surface pathway, which increases with age.

In the new study, the researchers found that in healthy aging, the time lag in circulation grows at almost the same rate as enlarging ventricles, but begins slightly earlier. A diagnostic MRI that measures an individual's lag between the two drainage pathways might be a good biomarker for the aging brain, and a possible predictor of ventriculomegaly. Because dementia resulting from hydrocephalus can be reversed by removing the fluid that builds up in the ventricles, early diagnosis is critical.

Recent studies reported that the incidence of dementia in western countries may be declining whereas low and middle income countries are predicted to have the largest increase in incident dementia. This discrepancy is suggested to be due to the differences in the effective management of cardiovascular disease, hypertension, and diabetes in these regions. However, even though early recognition of risk factors for dementia is of utmost priority, the sporadic incidence of dementia is a challenge in preventive medicine.

Previous studies have suggested that an association exists between vision loss and cognitive impairment. Low vision and blindness are commonly seen in the older population as the risk of developing cataract; age-related macular degeneration and glaucoma increase with advancing age. Despite the body of evidence, there are few reports regarding causal relationships or direct association between low vision and dementia. A clear understanding of this association may facilitate the development of strategies for reducing the burden of cognitive impairment.

The National Health Insurance Service (NHIS) database has recently become accessible to researchers in Korea. This large-scale database permits the identification of the longitudinal incidence of diseases and allows for the analysis of the association between diseases and health conditions. Using the six levels of disability of the Korean rating system, an individual with low vision can be classified depending on his/her visual acuity. Employing the disability grade used in Korea, we were able to investigate the impact of low vision on incident dementia by using a nationwide population-based cohort that includes over 1.5 million Koreans.

Statistical analysis showed that subjects with more severe visual impairments have a higher risk of dementia, Alzheimer's disease, and vascular dementia after adjusting for compounding variables. The hazard ratios (HRs) of dementia increased significantly as visual acuity worsened: 1.444 for visual acuity (VA) < 1.0, 1.734 for VA < 0.3, 1.727 for VA < 0.1, and 1.991 for visual loss. Baseline visual loss and visual impairment were positively associated with the risk of dementia, Alzheimer's disease, and vascular dementia. From the results of this nationwide population-based cohort study, we suggest that there is a significant increase in the incidence of dementia in subjects with low vision.

An international study that has been carried out on nearly 3000 people in Norway, Germany, and Iceland, shows that our kidney function deteriorates with age, even if we do not have any other diseases. One of the groups that have participated in the study consists of over 1600 people and stems from the Tromsø Study, which is Norway's most comprehensive and best participated population study throughout 40 years. This group has been through the different examinations three times; between 2007 to 2009, 2013 to 2015, and 2018 to 2020.

"What we see is that what happens in our kidneys when we age is representative of all the other things that happen in our bodies. The kidney function deteriorates, not because we get ill, but as part of ageing. Loss of kidney function is something that happens to all humans and is thus a way to determine ageing in general. There is still variation as to how quickly this happens, and we still do not have good answers as to why this variation occurs. We have examined many factors that can play a part as to why some of us experience larger loss of kidney function than others."

The researchers use a precise method of measuring kidney function. They inject a substance into the blood veins that only separates into the kidneys, and let a few hours pass before they measure how much of the substance remains in the blood. This gives a measure of the kidney's ability to remove toxins and waste products. Researchers explain that more people may experience loss of kidney function as it becomes more common to survive diseases like cancer and heart and vascular diseases.

The current classification of essential amino acids (EAA) is based on the nutritional requirements for growth and vitality under nil dietary supply of an amino acid. However, humans rarely face dramatic protein/amino acid insufficiency, and for the first time in human history, nutritional excesses mean the amount of overweight people outnumber the amount of underweight people on a global scale. This calls for a reconsideration of amino acid functions in nutrition, now based upon health-related criteria.

One approach is dietary protein dilution (DPD), where protein is reduced and replaced by other nutrient sources, and is distinct from caloric restriction. Unlike severe protein/amino acid restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies, rodents, and perhaps humans. Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related diseases such as cancer, type 2 diabetes, and dyslipidemia/fatty liver disease. Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans.

Here, by mimicking amino acid supply from a casein-based diet, we demonstrate that restriction of dietary EAA, but not non-EAA, drives the systemic metabolic response to total amino acid deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total amino acid supply, are both adequate and necessary to confer the systemic metabolic response to amino acid restriction.

Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

Autoimmune diseases are caused when the immune system loses its normal focus on fighting infections or disease within and instead begins to attack otherwise healthy cells within the body. In the case of multiple sclerosis (MS), the body attacks proteins in myelin - the fatty insulation-like tissue wrapped around nerves - which causes the nerves to lose control over muscles.

Scientists examined the intricate mechanisms of the T-cells that control the body's immune system and found that the cells could be 're-trained' to stop them attacking the body's own cells. In the case of multiple sclerosis, this would prevent the body from attacking the Myelin Basic Protein (MBP) by reprogramming the immune system to recognise the protein as part of itself.

The first stage showed that the immune system can be tricked into recognising MBP by presenting it with repeated doses of a highly soluble fragment of the protein that the white blood cells respond to. By repeatedly injecting the same fragment of MBP, the process whereby the immune system learns to distinguish between the body's own proteins and those that are foreign can be mimicked. The process, which is a similar type of immunotherapy to that previously used to desensitise people against allergies, showed that the white blood cells that recognise MBP switched from attacking the proteins to actually protecting the body.

The second stage, saw gene regulation specialists probe deep within the white blood cells that react to MBP to show how genes are rewired in response to this form of immunotherapy to fundamentally reprogram the immune system. The repeated exposure to the same protein fragment triggered a response that turns on genes that silence the immune system instead of activating it. These cells then had a memory of this exposure to MBP embedded in the genes to stop them setting off an immune response. When T cells are made tolerant, other genes which function to activate the immune system remain silent.

Taking blood pressure medication as prescribed helped even the frailest elderly people (65 and older) live longer, and the healthiest older people had the biggest survival boost, according to a large study in northern Italy. Researchers reviewed data on almost 1.3 million people aged 65 and older (average age 76) in the Lombardy region of northern Italy who had three or more high blood pressure medication prescriptions in 2011-2012. Examining the public health care database, researchers calculated the percentage of time over the next seven years (or until death) that each person continued to receive the medications. Because almost all medications are free or low-cost and dispensed by the public health service, this corresponds roughly to people's adherence in using the medication in Italy.

Researchers compared roughly 255,000 people who died during the 7-year follow-up with age-, gender-, and health-status-matched controls who survived and divided them into four groups of health status: good, medium, poor, or very poor. The probability of death over 7-years was 16% for people rated in good health at the beginning of the study. Mortality probability increased progressively to 64% for those rated in very poor health.

Compared with people with very low adherence to blood pressure medications, meaning dispensed pills covered less than 25% of the time period, people with high adherence to blood pressure medications, meaning more than 75% of the time period covered, were: (a) 44% less likely to die if they started in good health; and (b) 33% less likely to die if they started in very poor health. A similar pattern was seen with cardiovascular deaths. The greatest survival benefit was among the people who started in good health, and the most modest survival benefit was in those who started in very poor health. "Our findings definitely suggest that even in very frail people, antihypertensive treatment reduces the risk of death; however, the benefits may be smaller in this group."

One particularly large and often-ignored fraction of the human genome (more than 60%) is composed of repetitive elements (RE). These include: types 1 and 2 transposons (retrotransposons and DNA transposons, respectively), some of which can self-copy and reinsert into new locations; terminal repeats at the ends of retrotransposons; and tandem repeats, including sequences common to centromeres, chromatin, and other structured genome regions. Most RE are chromatinized and suppressed, but certain retrotransposons remain active in humans and may be involved in aging. Indeed, studies in mice and other model organisms have shown that active/transposable RE, in particular, contribute to the aging process, although most evidence points to RE activation later in life (e.g., in senescence).

The potential for RE in general to serve as a transcriptomic marker of aging has not been investigated, especially in humans, but we and others have reported a generic accumulation of RE transcripts (i.e., not only active RE) in age-related neurodegenerative processes and diseases. Evidence also indicates that chromatin maintenance declines with aging, which could increase general transcriptional accessibility of RE. As such, age-related changes in global RE transcript levels could be a good transcriptomic/mechanistic marker of aging.

Here, we used multiple RNA-seq datasets generated from human samples and Caenorhabditis elegans and found that most RE transcripts (a) accumulate progressively with aging; (b) can be used to accurately predict age; and (c) may be a good marker of biological age. The strong RE/aging correlations we observed are consistent with growing evidence that RE transcripts contribute directly to aging and disease.

In humans, the stiffness of the muscle-tendon complex in situ increases with aging, and this is mainly attributed to an increase in muscle stiffness, while tendons display greater compliance. Importantly, the age-related increase in stiffness of the muscle-tendon complex has been considered relevant to the preservation of eccentric force in the elderly. Whole muscle stiffness depends on the mechanical properties of muscle fibers and of extracellular matrix (ECM), and it is still debated whether muscle fibers or ECM are the determinants of such change.

To answer this question, we compared the passive stress generated by elongation of fibers alone and arranged in small bundles in young healthy (Y: 21 years) and elderly (E: 67 years) subjects. The physiological range of sarcomere length 2.5-3.3 μm was explored. The area of ECM between muscle fibers was determined on transversal sections with picrosirius red, a staining specific for collagen fibers.

The passive tension of fiber bundles was significantly higher in E compared to Y at all sarcomere lengths. However, the resistance to elongation of fibers alone was not different between the two groups, while the ECM contribution was significantly increased in E compared to Y. The proportion of muscle area occupied by ECM increased from 3.3% in Y to 8.2% in E. When the contribution of ECM to bundle tension was normalized to the fraction of area occupied by ECM, the difference disappeared. We conclude that, in human skeletal muscles, the age-related reduced compliance is due to an increased stiffness of ECM, mainly caused by collagen accumulation.

Maintaining a healthy lifestyle in older age is associated with a lower level of frailty. However, studies on the association between physical activity (PA) and frailty among older adults show contradictory results. Some studies suggest that regular PA may delay the onset of frailty and reduce its severity, but others found that PA was not associated with a decreased risk for frailty among older adults. Second, most of the longitudinal studies on PA and frailty examine baseline PA only in relation to changes in frailty, and evidence on the association between change in PA and frailty is limited. Additionally, most studies on PA and frailty have been conducted in adults aged 50 to 70 years, and evidence on the longitudinal association between PA and frailty in adults older than 70 years is relatively scarce.

Most previous studies on PA and frailty have focused on physical frailty only, and to date there has been little research into psychological and social frailty. Therefore, the aim of our study was to examine the longitudinal association between frequency of moderate PA and overall, physical, psychological, and social frailty among community-dwelling older adults older than 70 years. Second, we assessed the association between a 12-month change in frequency of moderate PA and frailty.

Participants who undertook moderate PA with a regular frequency at baseline were less frail at 12-month follow-up than participants with a low frequency. Participants who undertook moderate PA with a continued regular frequency were least frail at baseline and at 12-month follow-up. After controlling for baseline frailty and covariates, compared with participants with a continued regular frequency, participants with a decreased frequency were significantly more overall, physically, psychologically, and socially frail at 12-month follow-up. Participants with a continued low frequency were significantly more overall, physically, psychologically, and socially frail at 12-month follow-up. The 12-month follow-up frailty level of participants who undertook moderate PA with an increased frequency was similar to those with a continued regular frequency.

CD9, a tetraspanin membrane protein, is known to regulate cell adhesion and migration, cancer progression and metastasis, immune and allergic responses, and viral infection. CD9 is upregulated in senescent endothelial cells, neointima hyperplasia, and atherosclerotic plaques. However, its role in cellular senescence and atherosclerosis remains undefined.

We investigated the potential mechanism for CD9-mediated cellular senescence and its role in atherosclerotic plaque formation. CD9 knockdown in senescent human umbilical vein endothelial cells significantly rescued senescence phenotypes, while CD9 upregulation in young cells accelerated senescence. CD9 regulated cellular senescence through a phosphatidylinositide 3 kinase-AKT-mTOR-p53 signal pathway. CD9 expression increased in arterial tissues from humans and rats with age, and in atherosclerotic plaques in humans and mice.

Anti-mouse CD9 antibody noticeably prevented the formation of atherosclerotic lesions in ApoE knockout mice and Ldlr knockout mice. Furthermore, CD9 ablation in ApoE knockout mice decreased atherosclerotic lesions in aorta and aortic sinus. These results suggest that CD9 plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that CD9 is a novel target for prevention and treatment of vascular aging and atherosclerosis.