Fight Aging! Newsletter, July 22nd 2019

A substantial number of in vitro and in vivo assays have demonstrated the natural ability of cells to transfer mitochondria amongst each other. This phenomenon is most commonly observed in mitochondrial transfer from healthy mesenchymal stem/stromal cells (MSCs) to damaged cells. The transfer replaces or repairs damaged mitochondria and thereby reduces the percentage of dead cells and restores normal functions. In 1982, researchers introduced a type of artificial mitochondrial transfer or transplant (AMT/T) model using a co-incubation step between the recipient cell and exogenous mitochondria. Their pioneering study demonstrated for the first time that the mitochondrial DNA (mtDNA) of donor cells could be integrated into recipient cells and subsequently transmit hereditary traits and induce functional changes. AMT/T mimics the natural process of mitochondrial transfer, reprograms cellular metabolism, and induces proliferation. The introduction of this model elucidated the possible use of mitochondria as an active therapeutic agent.

Our study tests a modification of the original MitoCeption protocol which reduces the time and complexity of the protocol. We sought to determine if primary allogenic mitochondrial mix (PAMM) MitoCeption could be used to repair peripheral blood mononuclear cells (PBMCs) damaged by ultraviolet radiation (UVR). PAMM is composed of the PBMCs of at least three donors. Our results showed that when PBMCs are exposed to UVR, there is a decrease in metabolic activity, mitochondrial mass, and mtDNA sequence stability as well as an increase in p53 expression and the percentage of dead cells. When PAMM MitoCeption was used on UVR-damaged cells, it successfully transferred mitochondria from different donors to distinct PBMCs populations and repaired the observed UVR damage.

To our knowledge, this study is the first to demonstrate in-vitro that MitoCeption can be used to re-establish mitochondrial function loss caused by UVR exposure. Additionally, we successfully transferred a mix of different PBMC donors to one PAMM that was used to repair damaged cells. Other research groups have successfully transferred mitochondria from one cell donor type to others; however, none of them have mixed mitochondria isolated from different donors for the transfer/transplant. This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications.

In recent years, different approaches have been developed to counteract the progression of vascular atherosclerosis, including cholesterol-level lowering and inflammation modulation. Owing to the large numbers of inflammatory molecular and cellular mediators, it is unlikely that blockade of a single cytokine will be therapeutically effective. Long-living individuals (LLIs) delay or escape atherosclerosis-related cardiovascular disease (CVD). We have previously found that LLIs are enriched for a longevity-associated variant (LAV) in BPI fold containing family B, member 4 (BPIFB4).

We report here new exciting results on the pleiotropic activity of LAV-BPIFB4 on different mechanisms of the atherogenic process. These benefits were not associated with changes in the lipid profile. In addition, we provide ex vivo and in vitro evidence that these beneficial actions may extend to human vasculature until to be inversely associated to subclinical index of atherosclerosis in selected patients. Mechanistically, the effects of LAV-BPIFB4 seem to be attributable to a CXCR4-dependent mechanism.

LAV-BPIFB4 gene therapy succeeded in the two primary endpoints, namely improving endothelial dysfunction and reducing adverse vascular effects in ApoE knockout mice fed a high-lipid diet. Interestingly, LAV-BPIFB4 gene therapy did not affect the serum cholesterol profile, but it did contrast the ability of oxidized cholesterol to induce endothelial dysfunction by positively modulating the inflammatory/immune background of atherosclerosis. In line with this, LAV-BPIFB4 redistributed the pool of monocyte subpopulations, redirecting them towards a pro-resolving phenotype.

This was reflected by the increased abundance of CXCR4+Ly6C-high monocytes in bone marrow and spleen, the two major tissue reservoirs of monocytes available to mobilize towards injured tissues. In the margination process, CXCR4 is considered the retention force in the vasculature. Therefore, we speculate that the higher level of CXCR4 in blood Ly6C-high monocytes after LAV-BPIFB4 treatment in mice may finely tune the transit time into the circulation, completing a protective intravascular differentiation process. Consistent with their functionally distinct immunological roles, newly recruited Ly6C-high but not Ly6C-low monocytes uniquely differentiate into pro-resolving M2 macrophages, driving murine atherosclerotic regression at the early stages of the disease. Accordingly, we documented an enrichment of M2 splenic macrophages, which can contribute to dampen T cell activation and proliferation in a CXCR4-dependent manner. This latter result is in keeping with the reported ability of CXCR4 to promote the acquisition of the M2 phenotype in healthy monocyte-derived macrophages.

Increasing evidence about the molecular mechanisms of ageing suggests that many chronic diseases such as osteoarthritis (OA) are associated with the hallmarks of ageing, including cellular senescence and defective autophagy. Accumulation of senescent cells in tissues contributes to age-related diseases. Articular cartilage of patients with OA shows features of senescence. Senescence-associated secretory phenotype (SASP) factors released from chondrocytes, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, have been identified as major mediators contributing to the development and progression of OA. Similarly, intra-articular injection of senescent cells in mice results in OA-like pathology.

Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent the detrimental microenvironment changes occurring in joint dysfunction. A major step into the translation of senolytic treatments for OA was demonstrated by the beneficial effects of selective clearance of senescence chondrocytes using the Bcl-2 family inhibitor Navitoclax in animal models. The broad impact of senolytic treatment is also highlighted by the efficacy of dasatinib and quercetin combination in several models of age-related disease, which results in an extension of healthspan and lifespan in mice.

Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases. We aim to test this therapeutic hypothesis in preclinical models of OA, where senescence and autophagy play a relevant role. A novel cell-based dual imaging screening assay was developed to identify both senotherapeutics, able to either suppress markers of senescence (senomorphics) or to induce apoptosis of senescent cells (senolytics), and autophagy modulators.

Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients.

Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Blood from the PROspective Osteoarthritis Cohort of A Coruña (PROCOAC) and human cartilage from non-OA and knee OA patients were employed. Levels of PPARα were lower in OA patients compared to non-OA controls. The potential efficacy of PPARα agonists was also evaluated using the Osteoarthritis Initiative (OAI) Cohort. In this cohort, there were 35 fibrate users and 3322 participants not taking fibrates in the selected sample. Using a genetic matching, 35 fibrate users were matched to 35 participants in the control group. Interestingly, the results indicate that fibrate use by time interaction was associated with a statistically significant improvement of self-reported Western Ontario McMaster Osteoarthritis Index (WOMAC) function and WOMAC total scores. There was also a trend towards a decrease in WOMAC pain score. The results suggest that the fibrate use, when compared with non-use, was associated with a yearly decrease in WOMAC.

Advanced age is a major Alzheimer's disease (AD) risk factor; therefore, understanding cellular senescence and its impact on endothelial cells (ECs), neurons, glia, and immune cells is an essential prerequisite for elucidating the pathogenesis of this condition. Brain accumulation of extracellular β-amyloid and intracellular hyperphosphorylated tau are the pathological hallmarks of AD. Both neurons and astrocytes synthesize β-amyloid from amyloid precursor protein (APP), while phagocytic microglia prevent its accumulation by removing it via the triggering receptor expressed on myeloid cells-2 (TREM-2).

The amyloid hypothesis postulates that accumulation and deposition of β-amyloid are the primary causes of AD, which promotes tau aggregation into neurofibrillary tangles (NFTs), ultimately triggering neuronal death. Although never universally accepted, the amyloid hypothesis drove AD research for at least two decades. Lately, however, many researchers and clinicians have questioned this model as amyloid removal failed to improve memory in numerous clinical trials. With the same token, neuroimaging studies detected significant β-amyloid deposits in 20-30% of healthy older individuals, while in many AD patients, this marker was not observed.

Moreover, β-amyloid was recently characterized as an antimicrobial peptide (AMP), and its accumulation in AD brains may be a reflection of increased microbial burden. AMPs are defensive biomolecules secreted by the innate immune system, including microglia and astrocytes, in response to a variety of microorganisms and malignant cells. The β-amyloid-AMP connection is further supported by the observation that central nervous system (CNS) infections were diagnosed in some clinical trials, following the administration of anti-amyloid vaccines.

Recent studies have reported co-localization of microorganisms with senescent neurons and glial cells in the brains of both AD patients and healthy older individuals, reviving the infectious hypothesis. CNS infectious agents have been detected previously in AD patients; however, it was difficult to assess if they represented the cause or effect of this condition. A recent study may have settled this issue as it detected gingipain, a Porphyromonas gingivalis antigen, linked to AD, in the brains of healthy older persons, suggesting that they would have developed the disease if they lived longer. As P. gingivalis is a major cause of gum disease and a modifiable AD risk factor, treatment of periodontal infection must be considered a clinical priority.

It has been well-established that inflammation and cellular senescence are closely related, but the role of pathogens in this process has been less emphasized. Astrocytes are the most numerous brain cells. Recent studies report that astrocytes are innate immune cells that, along with microglia, play a key role in the phagocytic removal of molecular waste, dead, or dying cells. Preclinical studies have reported that astrocytes undergo both replicative senescence and stress-induced senescence, however, the difference between senescent and reactive astrocytes is not entirely clear at this time. Recent studies seem to indicate that these phenotypes may be closely related or even identical as upregulated inflammatory and synapse-eliminating genes were found in both senescent and reactive astrocytes.

Dystrophic microglia with growth arrest and senescent markers have been demonstrated in AD patients, but the difference between the reactive and dystrophic phenotype is unclear at this time. Taken together, senescent microglia, incapable of proper immunosurveillance and phagocytosis, contribute to the accumulation of molecular waste, dead or dying cells, inducing inflammaging and immunosenescence. Astrocytes may respond to these microenvironmental changes by converting to a phenotype marked by aberrant elimination of healthy synapses and neurons, a possible pathogenetic mechanism of AD.

Thus, microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. We take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. Commensal gut microbes live in symbiosis with the human host as long as they reside in the GI tract where they can be kept under control. Cellular senescence alters the integrity of biological barriers, allowing translocation and dissemination of gut microorganisms throughout the body tissues, including the brain. Operating "behind enemy lines," pathogens can gain control of host immune defenses and metabolism, triggering senescence and neurodegenerative pathology.

The beneficial cognitive effects of physical exercise cross the lifespan as well as disease boundaries. Exercise alters neural activity in local hippocampal circuits, presumably by enhancing learning and memory through short and long-term changes in synaptic plasticity. The dentate gyrus is uniquely important in learning and memory, acting as an input stage for encoding contextual and spatial information from multiple brain regions. This circuit is well suited to its biological function because of its sparse coding design, with only a few dentate granule cells active at any one time. These properties also provide an ideal network to investigate how exercise-induced changes in activity-dependent gene expression affect hippocampal structural and synaptic plasticity in vivo.

While exercise is a potent enhancer of learning and memory, we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked the activated mature dentate granule cells of the hippocampus using conditional Fos-TRAP mice. Exercise-activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity.

Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied I-BAR domain-containing gene, which we hypothesized could be involved in membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses.

In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers.

In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuclear factors. The shelterin complex is essential for telomere protection and comprises six subunits: Three subunits bind telomeric DNA (TRF1, TRF2, and POT1), while the three others establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1, TRF2, and TPP1 with TIN2 and POT1. Each shelterin subunit has a specific role in telomere protection, i.e., TRF1 prevents replication stress, TRF2 blocks ataxia telangiectasia-mutated (ATM) signaling and non-homologous end joining (NHEJ), while POT1 blocks ataxia telangiectasia and Rad3-related (ATR) signaling.

A wealth of recent findings points toward shelterin as a valuable alternative to telomerase to fight cancer. Researchers have identified small molecule compounds targeting TRF1 using an FDA-approved library to screen for TRF1 expression and localization. Several of the drugs downregulating TRF1 expression interfere with common cancer signaling pathways. Treatment of lung cancer and glioblastoma cells with these compounds triggered DDR activation at telomeres and telomere replication defects. In patient-derived glioblastoma stem cells (GSC), these TRF1 inhibitors reduced stemness in vitro.

Researchers have discovered how regenerative capacity of intestinal epithelium declines when we age. Targeting of an enzyme that inhibits stem cell maintaining signaling rejuvenates the regenerative potential of an aged intestine. This finding may open ways to alleviate age-related gastrointestinal problems, reduce side-effects of cancer treatments, and reduce healthcare costs in the ageing society by promoting recovery.

The age-induced reduction in tissue renewal makes dosing of many common drugs challenging. Targeting of an inhibitor called Notum may provide a new way to increase the therapeutic window and to promote recovery in societies with the aging population. Researchers believe that in addition to direct targeting of Notum, lifestyle factors such as diet may also provide means to reduce Notum, and thus improve tissue renewal and repair.

Using organoid culture methods, researchers understood that poor function of tissue repairing stem cells in old intestine was due to aberrant signals from the neighboring cells, known as Paneth cells. "Modern techniques allowed us to examine tissue maintenance at a single cell level, and revealed which cell types contribute to the decline in tissue function. We were surprised to find that even young stem cells lost their capacity to renew tissue when placed next to old neighbors."

Normally intestinal epithelium is renewed by stem cells that rely on activity of Wnt-signaling pathway. Surrounding cells produce molecules that activate this pathway. The study shows that during ageing, Paneth cells begin to express a secreted Wnt-inhibitor called Notum. Notum enzymatically inactivates Wnt-ligands in the stem cell niche, decreasing regenerative potential of intestinal stem cells. However, pharmacologic inhibition of Notum rejuvenated stem cell activity and promoted the recovery of old animals after treatment with a commonly used chemotherapeutic drug with severe side-effects in the gut.

Ghrelin is produced in the stomach and secreted in anticipation of eating, and is known for its role to increase hunger. For example, ghrelin levels would be high if you were at a restaurant, looking forward to a delicious dinner that was going to be served shortly. Once it is secreted, ghrelin binds to specialized receptors on the vagus nerve - a nerve that communicates a variety of signals from the gut to the brain. Researchers recently discovered that in addition to influencing the amount of food consumed during a meal, the vagus nerve also influences memory function. The team hypothesized that ghrelin is a key molecule that helps the vagus nerve promote memory.

Using an approach called RNA interference to reduce the amount of ghrelin receptor, the researchers blocked ghrelin signaling in the vagus nerve of laboratory rats. When given a series of memory tasks, animals with reduced vagal ghrelin signaling were impaired in a test of episodic memory, a type of memory that involves remembering what, when, and where something occurred, such as recalling your first day of school. For the rats, this required remembering a specific object in a specific location.

The team also investigated whether vagal ghrelin signaling influences feeding behavior. They found that when the vagus nerve could not receive the ghrelin signal, the animals ate more frequently, yet consumed smaller amounts at each meal. Researchers think that these results may be related to the episodic memory problems. "Deciding to eat or not to eat is influenced by the memory of the previous meal. Ghrelin signaling to the vagus nerve may be a shared molecular link between remembering a past meal and the hunger signals that are generated in anticipation of the next meal."

In the nucleus of cells, DNA wraps itself around histone proteins forming a 'beads-on-a-string' structure called chromatin. Other proteins bind along chromatin and the structure folds further into more complicated configurations. Everything involving DNA would have to deal with this chromatin structure. For example, when a particular gene is expressed, certain enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress happens, disruption of the chromatin structure can lead to unwanted changes in gene expression, such as expression of genes when they are not supposed to or lack of gene expression when it should occur.

In this study, researchers worked in the lab with the yeast Saccharomyces cerevisiae to investigate how the dosage of histone genes would affect longevity. They expected that yeast genetically engineered to carry fewer copies of certain histone genes than normal or control yeast would have chromatin changes that would result in the yeast living less than controls. "Unexpectedly, we found that yeast with fewer copies of histone genes lived longer than the controls." Yeast with a moderately low dose of histone genes showed a moderate reduction of histone gene expression and significant chromatin stress. Their response to chromatin disruption was changes in the activation of a number of genes that eventually promoted longevity.

"We have identified a previously unrecognized and unexpected form of stress that triggers a response that benefits the organism. The mechanism underlying the chromatin stress response generated by moderate reduction of histone dosage is different from the one triggered by histone overexpression we had previously described, as shown by their different profiles of protein expression responses." The researchers found that chromatin stress also occurs in other organisms such as the laboratory worm C. elegans, the fruit fly, and mouse embryonic stem cells, and in yeast and C. elegans the chromatin stress response promotes longevity. "Our findings suggest that the chromatin stress response may also be present in other organisms. If present in humans, it would offer new possibilities to intervene in the aging process."

"We've reached the perfect storm in aging science," says physician Nir Barzilai. "Everything is happening. We have the foundation from decades of animal studies. We're ready to move on to people." The ultimate goal: to put the brakes on aging itself - preventing the pileup of chronic health problems, dementia and frailty that slam most of us late in life. "I want 85 to be the new 65," says Joan Mannick, the chief medical officer and cofounder of resTORbio.

The need is enormous. In a decade, nearly 1 in 5 Americans will be 65 or older. Three out of 4 will have two or more serious health conditions. At least 1 in 4 can expect memory lapses and fuzzy thinking, while 1 in 10 will develop dementia. "Right now doctors play whack-a-mole with chronic diseases in older adults. You treat one, another pops up. The goal instead is to tackle aging itself, the major risk factor for almost every major disease. Our society, our drug companies and medical profession aren't addressing all this suffering that happens as people grow old. But the older people in my life are beloved to me. If we can do something about aging, we shouldn't ignore it."

Older people who took the mTOR inhibitor RAD001, a similar drug to resTORbo's RTB101, had a stronger response to a flu vaccine. Their immune systems looked younger, with fewer exhausted T cells - a depressingly common feature of aging called immunosenescence. "This was the first evidence that if you target a pathway in humans, you may actually impact how we age." The results of a trial of RTB101 were particularly strong for people 85 and older; they had 67 percent fewer infections. That's good news, because - in part due to an age-related weakening of the immune system - respiratory infections are the fourth-leading reason older U.S. adults wind up in the hospital and their eighth-leading cause of death.

Alas, there's more going wrong in older cells than on-the-fritz mTOR. Among these issues: inflammation; out-of-whack metabolism; inactive stem cells that can't repair body tissues; damage from stress, environmental toxins and free radicals; reduced "quality control," which can't eliminate rogue cells. These glitches boost the risk for everything from heart disease and stroke to diabetes, osteoarthritis, Alzheimer's disease, Parkinson's and cancer. If these and other cellular issues are the underlying causes of so many diseases, preventing cells from succumbing to them as they age is a key to preventing disease. That's why resTORbio, other biotech start-ups and university aging labs across the U.S. are launching an unprecedented number of human clinical trials with experimental compounds aimed at these mechanisms.

One big target: senescent cells that refuse to die, instead glomming up in joints and other body tissues. They pump out dozens of inflammatory compounds and other chemicals that contribute to age-related diseases. In a raft of mouse studies, clearing out these senescent cells boosted health - easing arthritis pain, improving kidney and lung function, increasing fitness, extending life and even making fur thicker. In January, the first-ever human study of a treatment to kill senescent cells in the lungs was published. Fourteen people with the fatal lung disease idiopathic pulmonary fibrosis took a mix of the drugs dasatinib and quercetin for three weeks. The verdict: The drug combo was safe, triggered just one serious side effect (pneumonia), and seemed to improve study volunteers' basic ability to stand up and walk. There were also hints it may have reduced senescent-cell activity, but the researchers say bigger, longer studies are needed.

Right now, simply staying healthy into our 80s, 90s and beyond is a lot like hitting the lottery jackpot. In a survey of 55,000 Americans age 65-plus, just 48 percent rated their health as very good or excellent. No wonder drugstores, the internet, and human history are littered with unproven rejuvenation come-ons. Meanwhile, as researchers slowly test these more legitimate drugs, what can we do today if we wish to retain good health longer? That answer has been with us all along. Not smoking, eating healthy, getting exercise, managing stress and sleep.

Mesenchymal stem cells (MSCs) are located in specific areas of tissues, called "niches", and are characterized as being in a state of relative quietness, from which they can exit under the proper conditions to obtain the proliferative potential necessary for tissue regeneration. MSCs have sustained interest among researchers by contributing to tissue homeostasis and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors, because their paracrine action is the main mechanism explaining their effects, regardless of source.

Senescence is defined as a mechanism for limiting the regenerative potential of stem cells. It is now evident that senescent cells secrete dozens of molecules, for which the terms "senescence-associated secretory phenotype (SASP)" and "senescence-messaging secretome (SMS) factors" have been proposed. The secreted factors contribute to cellular proliferative arrest through autocrine/paracrine pathways as well as in vivo and in vitro. SMS factors released by senescent cells play a key role in cellular senescence and physiological aging by activation of cytoplasmic signalling circuitry.

The population of mesenchymal stem cells, also known as mesenchymal stromal cells, contributes directly to the homeostatic maintenance of organs; hence, their senescence could be very deleterious for human bodily functions. The milestone in MSC investigation will be discovering senescence markers to determine the quality of the in vitro cells for cell-based therapies. Researchers have proposed TRAIL receptor CD264 as the first cellular senescence mesenchymal marker in bone marrow-derived MSCs, because it has the same expression profile of p21 during culture passage.

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells.

MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs.

Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. The causes of cellular aging and the concomitant decline in functionality are wide-ranging, but provide some intriguing indications of potential targets for speeding fracture healing in older individuals. In the future, cell therapies that supplement the inadequate native cellular response with MSCs or endothelial colony forming cells (ECFCs); bone anabolic pharmacological agents, particularly in combination with strategies to localize their delivery to the bone fracture; drugs that reduce oxidative stress, cellular senescence, or activate SIRT1; and/or physical therapeutics may prove effective in promoting fracture healing in the elderly.

Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

In a massive new analysis of findings from 277 clinical trials using 24 different interventions, researchers say they have found that almost all vitamin, mineral, and other nutrient supplements or diets cannot be linked to longer life or protection from heart disease. Although they found that most of the supplements or diets were not associated with any harm, the analysis showed possible health benefits only from a low-salt diet, omega-3 fatty acid supplements and possibly folic acid supplements for some people. Researchers also found that supplements combining calcium and vitamin D may in fact be linked to a slightly increased stroke risk.

Surveys show that 52% of Americans take a least one vitamin or other dietary/nutritional supplement daily. An increasing number of studies have failed to prove health benefits from most of them. "The panacea or magic bullet that people keep searching for in dietary supplements isn't there. People should focus on getting their nutrients from a heart-healthy diet, because the data increasingly show that the majority of healthy adults don't need to take supplements."

The vitamin and other supplements reviewed included: antioxidants, β-carotene, vitamin B-complex, multivitamins, selenium, vitamin A, vitamin B3/niacin, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, calcium and vitamin D together, folic acid, iron and omega-3 fatty acid (fish oil). The diets reviewed were a Mediterranean diet, a reduced saturated fat (less fats from meat and dairy) diet, modified dietary fat intake (less saturated fat or replacing calories with more unsaturated fats or carbohydrates), a reduced fat diet, a reduced salt diet in healthy people and those with high blood pressure, increased alpha linolenic acid (ALA) diet (nuts, seeds and vegetable oils), and increased omega-6 fatty acid diet (nuts, seeds and vegetable oils). Each intervention was also ranked by the strength of the evidence as high, moderate, low or very low risk impact.

The majority of the supplements including multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone and iron showed no link to increased or decreased risk of death or heart health. "Our analysis carries a simple message that although there may be some evidence that a few interventions have an impact on death and cardiovascular health, the vast majority of multivitamins, minerals and different types of diets had no measurable effect on survival or cardiovascular disease risk reduction."

Over the course of an individual's life, skeletal muscle undergoes numerous injurious insults that require repairs in order for function to be maintained. The maintenance and injury repair of skeletal muscle is dependent on its resident stem cell (i.e., the satellite cell). With proliferation, satellite cells undergo asymmetric division through which a subpopulation of the daughter satellite cells do not differentiate, but instead return to quiescence, repopulating the satellite cell pool (i.e., self-renewal). The balance of this asymmetric division process is critical and necessary to ensure the life-long preservation of satellite cells in skeletal muscle.

Aging diminishes the satellite cell pool and, as a result, the regenerative capacity of skeletal muscle in aged males is impaired compared to that of younger males, but such age-induced impairments in females is less studied. Similarly, age-associated changes in the satellite cell environment, in combination with cell-intrinsic alterations, disrupt quiescence and the balance of asymmetric division, ultimately impacting satellite cell maintenance and muscle regenerative potential. Such results support the concept that circulatory factors, including hormones that differ between the young and old systemic environments and the activity of their subsequent signaling pathways, contribute to age-associated decrements in satellite cell maintenance and overall muscle regenerative capacity.

A well-known hormone that changes with age is estradiol, the main circulating sex hormone in adult females. Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause. Estradiol deficiency reduces skeletal muscle mass and force generation in women and prevents the recovery of strength following contraction-induced muscle injury and traumatic muscle injury in female mice. However, evidence that this regenerative phenotype involves effects of estradiol directly on satellite cells is lacking.

In this study, we use rigorous and unbiased approaches to demonstrate the in vivo necessity of estradiol to maintain the satellite cell number in females. Further, we use mouse genetics to show that the molecular mechanism of estradiol action is cell-autonomous signaling through estrogen receptor α (ERα). Specifically, we show the functional consequence of estradiol-ERα ablated signaling in satellite cells including impaired self-renewal, engraftment, and muscle regeneration, and the activation of satellite cell mitochondrial caspase-dependent apoptosis. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.