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- MItochondria in Age-Related Hearing Loss
- Alzheimer's Therapies are Achieving Goals in Patient Biochemistry, But Not in Outcomes
- Nrf2, Excessive Autophagy in Skeletal Muscle, and Age-Related Sarcopenia
- To What Degree is Chondrocyte Hypertrophy in Osteoarthritis Due to Cellular Senescence?
- Speculating on Circumstances in Which Group Selection of Aging Can Occur
- Potential Mechanisms to Restore Lost Function in Aged Hematopoietic Stem Cells
- Age-Related Changes in the Gut Microbiome and Alzheimer's Disease
- Heart Attack Risk is Age-Related, but Aging Also Makes Treatments Less Effective
- Chronic Kidney Disease Accelerates Many Aspects of Aging, Such as Cardiovascular Disease Risk
- Cyclin D1 as a Potential Basis for an Exercise Mimetic
- Indicators of Frailty Start to Appear Early, Probably Due to Lifestyle Choices
- An Update on Oisin Biotechnologies and OncoSenX
- The Importance of Mitophagy in Aging
- GDF11 in the Regeneration and Aging of Skin
- A Cardiac Patch Without Cells Improves Regeneration Following Heart Attack
MItochondria in Age-Related Hearing Loss
In today's open access paper, researchers present evidence to suggest that the mitochondrial dysfunction that accompanies aging may be a meaningful cause of the loss of neurons that contributes age-related hearing loss, in the sense that it increases the incidence of necroptosis, a form of programmed cell death. Present thinking on the progressive deafness of old age is that the sensory hair cells of the inner ear largely remain intact, but their connection to the brain atrophies - the nerve cells in question dying in excessive numbers for reasons that continue to be explored.
Mitochondria are the power plants of the cell, producing chemical energy store molecules necessary for cellular processes to run, but they are also deeply involved in the various ways in which cells can undergo programmed cell death. With age, mitochondria become less efficient, they become larger the balance between fission and fusion changes, and the quality control mechanism of mitophagy, responsible for removing damaged mitochondria, falters. This contributes to most of the manifestations of aging in some way, and thus it is important for the research community to push ahead in the development of potential means of restoring mitochondrial function in older people.
Mitochondrial Damage and Necroptosis in Aging Cochlea
Approximately one in five people over the age of 50 has imperfect hearing, and almost half of those aged over 65 years have hearing difficulties. Presbycusis, also termed age-related hearing loss (ARHL), is an irreversible hearing impairment associated with aging due to limited repair capacity of sensorineural tissues in the cochlea. Unfortunately, there is no effective cure for the patients, and future treatment development is still questionable due to lack of mechanistic insight. In order to identify pathologic changes in the aged cochleae, we utilized C57BL/6J mice to investigate the pathophysiology of ARHL, as this strain displays accelerated, high-frequency hearing loss by 3-6 months of age and profound hearing impairment by 15 months of age.
Mitochondria are involved in the metabolic dysregulation associated with ARHL pathology. Morphologically, damage is apparent in the outer hair cells (OHCs) of animal ARHL models. Mitochondria are the principal source of reactive oxygen species (ROS), the production of which is closely associated with ARHL progression. Antioxidants alleviate the deleterious effects of ROS and effectively treat oxidative stress-related diseases in an animal model of ARHL. As mitochondria play key roles in both the respiratory chain and cell death, animal models of ARHL often exhibit defects in mitochondrial enzyme activities and mitochondrial-mediated apoptosis.
Neuronal cell death occurs through various pathways in sensorineural tissue, leading to hearing impairment. Necroptosis is a programmed cell death that exhibits necrosis-like morphological characteristics. The most defined molecular pathway of necroptosis is mediated by TNF-α receptor through receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL).
We identified increased RIPK3 level in the aging cochlea, especially in the inner and outer hair cells and stria vascularis. Pronounced reduction in cytochrome c oxidase subunits 1 (COX1) and 4 (COX4), indicating that the mitochondria of the aging cochleae were dysfunctional, correlated with the degree of mitochondrial morphological damage. Hearing impairment found in aging animals was associated with a loss of sensory hair cells and neuronal filaments. Our data suggest that mitochondrial degeneration and necroptosis may play a critical role in the pathophysiology of ARHL and provide mechanistic insights for future therapeutic development.
Alzheimer's Therapies are Achieving Goals in Patient Biochemistry, But Not in Outcomes
If a therapy targets an important cause of a condition, and does so effectively, there should be little ambiguity in the results that emerge from clinical trials. The size of effect will be large, there will be no need to frown and interpret and try to find subgroups in the which the results are enough to declare some sort of success. Sadly, this latter position is much the state of the Alzheimer's clinical development community, still largely focused on immunotherapies targeting amyloid-β. Such an enormous amount of funding is devoted to these efforts that there is considerable incentive for the sponsoring entities to find some way to declare success, any success, at the end of the day. But are patients doing any better? Not really.
The trend in the field is towards an ability to measurably reduce aggregated amyloid-β and tau in the brain, as well as other biomarkers associated with neurodegeneration, but to see no benefit to cognitive function as an outcome. Why this is the case remains an open question, given the very robust evidence for amyloid-β and tau to be driving the progression of the condition. Or are they? Perhaps Alzheimer's disease is a self-sustaining inflammatory condition in which the immune cells of the brain have been driven into sufficient dysfunction that removing the trigger of aggregated amyloid-β and tau will do little. Or perhaps vascular dysfunction is a lot more important than has been thought, and success will be elusive until it is also addressed. It is with this in mind that one has to parse remarks on trial data.
Confused About the DIAN-TU Trial Data? Experts Discuss Nuances
At the virtual AAT-AD/PD Focus meeting, clinicians and funders involved in the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) discussed results from the first DIAN-TU treatment and prevention trial of the monoclonal antibodies solanezumab and gantenerumab. DIAN-TU's principal investigator had presented topline data analyses of the primary outcome, which was head-scratchingly negative. He also presented the first analyses of several of the trial's biomarker measures, which were robustly positive. What does it all mean?
"It was gratifying to see all biomarkers that were presented moving toward normal. Brain amyloid down, cerebrospinal fluid (CSF) Aβ42 up, tau and p-tau down, and the neurofilament light protein (NfL) increase prevented. This shows the biology of the antibody is working. The whole field is witnessing that antibodies designed to remove amyloid do their jobs and are followed by other biomarkers going in the right direction. Why did this not translate into clinical benefit? Is there a threshold we need to hit? Do we need to go down to zero? Or is it dose exposure over time?"
In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned
Topline data suggest that the first two drug arms of the DIAN-TU trial platform - solanezumab and gantenerumab - were not a complete bust. Instead, the analyses finished to date point to nuanced effects of dose, time, disease stage, and biology. To be sure, the data did substantiate the earlier announcement that both therapeutic antibodies had fallen short on the trial's primary endpoint, the DIAN-TU multivariate cognitive endpoint. What happened? In short, symptomatic participants had descended into moderate dementia even before they could be titrated up to a high dose, whereas asymptomatic participants stayed stable throughout the trial regardless of whether they were on drug or placebo. This left the trial's main question unanswered.
For solanezumab, a monoclonal antibody targeting soluble amyloid-β, this indeed marks the end of its exploration within DIAN, the global research network for families with autosomal-dominant Alzheimer's disease. But all is not lost for gantenerumab, a monoclonal targeting aggregated forms of amyloid-β. Besides removing amyloid plaques from the brain and normalizing CSF Aβ42, this antibody reversed toward normal the elevated levels of CSF total tau and p-tau181, an AD-specific, pathological form of this neuronal protein. Gantenerumab further stemmed the rise of the general neurodegeneration marker CSF neurofilament light.
The effect sizes of this biomarker response were so large that they prompted the DIAN investigators to invite DIAN participants - who have devoted four to seven years of their lives to this trial, depending on when they enrolled - to join an open-label extension. It will explore high-dose gantenerumab therapy for several additional years. Its goal? To see if sustained gantenerumab therapy near the highest tolerated dose removes both plaques and tangles all the way down to a hypothesized, yet-to-be-defined threshold at which cognition and function might start to benefit.
Nrf2, Excessive Autophagy in Skeletal Muscle, and Age-Related Sarcopenia
Autophagy is the name given to a collection of processes responsible for recycling damaged, harmful, or unwanted proteins and structures in cells. In general autophagy declines with age and this is a problem, allowing long-lived cells to accumulate damage and dsyfunction. There is considerable focus in the research community on ways to enhance autophagy, based on evidence that upregulation of autophagy occurs as a beneficial response to stress, improving health and lengthening life. Calorie restriction is the most studied example of this response.
Nothing is simple and universal in biochemistry, however. In muscle tissue, autophagy instead increases with age, to the point at which it becomes harmful to cell and tissue function. This may be one of the contributions to sarcopenia in older individuals, the progressive loss of muscle mass and strength - though the size of the effect in comparison to the many other contributing factors can be debated. In today's open access paper, the authors report on their investigation of the proximate causes of this excessive autophagy. They point to a loss of Nrf2 expression, which may or may not be a useful target for potential interventions.
Nrf2 deficiency promotes the increasing trend of autophagy during aging in skeletal muscle: a potential mechanism for the development of sarcopenia
Autophagy is an evolutionary conserved process of cellular degradation and recycling, whereby misfolded proteins and exhausted organelles are degraded to maintain cellular homeostasis. Skeletal muscle is the most abundant tissue in human body, accounting for about 40-55% of the body weight. Autophagy plays a key role in the regulation of muscle mass, either excessive or impaired autophagy leads to muscle mass wasting. Deficiency in the basic autophagy function causes accumulation of misfolded proteins and exhausted organelles and results in skeletal muscle cell dysfunction and death. On the contrary, excessive autophagy can also be deleterious by causing cellular stress and muscle protein degradation.
Muscle mass declines with increasing age, which is termed sarcopenia. Several animal models have showed that ablation of autophagy function results in precocious aging and muscle wasting in mice. However, it is still controversial about the changes of autophagy function in skeletal muscle with increasing age. Based on the evidence from lower organisms and non-muscle tissue, most literature held the concept that skeletal muslcle autophagy declines with aging. On the contrary, a recent study showed that autophagy and mitophagy in mice muscle were enhanced during aging, which may contribute to the decline in organelle contents and muscle mass, but serve to maintain a healthy organelle pool and muscle cells function.
Inconsistent results in the literature suggested that the measurement of autophagy-related proteins at the static level can often lead to discrepancies in interpretation, because autophagy is a dynamic process. Therefore, measurement of autophagy flux is necessary to reflect the real condition of autophagy within muscle cells during aging. Until a recent study, no previous studies have investigated the alterations of autophagy during aging in skeletal muscle using autophagy flux measurement. In contrast with most previous studies, our study showed that increasing age lead to a trend of increased autophagy in skeletal muscle, using autophagy flux measurements.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a cytoprotective gene which mainly functions to protect cells against oxidative stress and toxicants. In recent years, increasing evidence has revealed the role of Nrf2 in the regulation of autophagy. Our study showed that Nrf2 knockout decreased the levels of autophagy-related proteins, which was in consistent with previous studies. However, the explanation of our results was different from previous studies. Using autophagy flux measurements, we proved that Nrf2 knockout significantly increased autophagy in the muscle tissue. Therefore, we attributed the decreased levels of autophagy-related proteins in the Nrf2 knockout mice to the faster clearance of these proteins by autophagy.
Several previous studies have investigated the effect of aging on the expression of Nrf2 and its downstream cytoprotective genes in the skeletal muscle but the results were inconsistent. In recent years, increasing studies have recognized that expression of Nrf2 and its downstream genes in the skeletal muscle can be activated by physical exercise. Elderly humans who have a physically active lifestyle have an even higher expression level of Nrf2 and its downstream cytoprotective proteins compared with young subjects. This can partially explain the inconsistent previous studies regarding the effect of aging on the expression of Nrf2 and its downstream cytoprotective genes.
In conclusion, our study demonstrated that Nrf2 deficiency promoted the increasing trend of autophagy during aging in skeletal muscle. Nrf2 deficiency and increasing age may cause excessive autophagy in skeletal muscle, which can be a potential mechanism for the development of sarcopenia.
To What Degree is Chondrocyte Hypertrophy in Osteoarthritis Due to Cellular Senescence?
Senescent cells are large. They do not replicate, that function is disabled, but it is as if they go to the effort of producing all the material needed for replication, and thus swell up in size. A lot of the distinctive behavior of senescent cells seems quite connected to the fact that they are large. Insofar as aging is concerned, the important aspects of senescent cells are (a) whether or not they are being cleared rapidly and efficiently enough to keep their numbers down, and (b) the inflammatory, damaging signals they secrete. As senescent cell numbers grow, they cause ever more dysfunction in the surrounding tissue and the body at large.
In today's open access paper, researchers tie together observations of enlargement in the chondrocyte cells that make up cartilage tissue, that growth in size involved in the transformation of cartilage to bone, with the incidence of cellular senescence in those cells. Osteoarthritis, involving chronic inflammation and degeneration of cartilage, may be largely driven by cellular senescence. If examining large chondrocytes, there is no doubt some degree of overlap between dysfunction in which too much transformation to bone is taking place, versus rising levels of cellular senescence. But how much overlap?
Research into cellular senescence is at a peculiar stage at the moment. Senescent cells are clearly involved in near every age-related disease, but the research community at large has only become earnestly engaged in this topic over the last five years or so. There are a great many diseases of aging, and only so many scientists. So cellular senescence, despite being of great importance to the treatment of aging, is still poorly explored in the specific context of most conditions. Researchers are likely to learn more by deploying one of the proven senolytic drugs to destroy senescent cells than they are through analysis of the disease state without intervention - but again, many diseases and only so many research teams.
The Role of Chondrocyte Hypertrophy and Senescence in Osteoarthritis Initiation and Progression
Osteoarthritis (OA) is the most common joint disorder throughout the whole human population. OA accompanies progressive degradation of the articular cartilage, which leads to a loss of joint mobility and function and eventually to a low quality of life in patients due to both pain and restricted lifestyles. Healthy chondrocytes usually display moderate metabolic activity and proliferation under normal conditions; however, some articular chondrocytes lose their differentiated phenotype under diseased conditions and enter an endochondral ossification (EO)-like state of proliferation along with abnormal hypertrophic differentiation. Cellular senescence can also occur alongside hypertrophy due to similar stimuli. Cellular senescence and hypertrophy share various markers and processes, and both events are reported to play a role in the development of OA.
Chondrocyte hypertrophy and cell death are natural phenomena that usually occur during a developmental process called EO. Hypertrophic chondrocytes appear and play a crucial role in EO. Hyaline cartilage can be divided into two groups, (1) temporary and (2) permanent cartilage. Healthy cartilage is usually called permanent cartilage or resting chondrocytes, which are present in the articulating joint. Usually, permanent cartilage has a low proliferation rate and does not undergo terminal differentiation and EO. Temporary cartilage is initially formed as cartilage, but the final product is bone. Chondrocytes undergo active proliferation and generate a cascade of cells; whereas some of them undergo enlargement, others undergo hypertrophical changes and become hypertrophic chondrocytes. These cells increase their volume dramatically and the surroundings become mineralized to develop bone tissue.
Although various cell types are involved in OA pathology, chondrocytes are primarily thought to play a major role in OA induction by cellular senescence. When senescent cells were transplanted into the knee joint of wild type mice, an OA-like state was induced, which included pain, impaired mobility, and morphological and histological changes. The senescence-associated secretory phenotype of senescent cells can alter the tissue microenvironment and impair tissue regeneration induced by stem cells or progenitor cells, which can eventually lead to the senescence of the neighboring cells. Beside chondrocytes, synovial fibroblasts are also thought to initiate or progress OA through senescence. Nuclear expression of p16 was detected in higher amounts in OA synovial tissue samples when compared to that of normal synovial tissues, which indicates senescence in OA synovial fibroblasts.
The molecular mechanisms of OA initiation and progression require considerable further study, despite significant progress in recent years. OA is mainly caused by trauma induced by an external force or cartilage damage accumulated during aging. During these processes, chondrocyte hypertrophy and senescence are thought to play a critical role in OA initiation or progression. However, the remaining question is: which came first, the chicken or the egg? There is still little understanding of whether these two independent processes (i.e., chondrocyte hypertrophy and senescence) are dependent on penetration in the other. Further study on which event is the cause or the effect should be conducted to better understand these processes.
Speculating on Circumstances in Which Group Selection of Aging Can Occur
The consensus view on the evolution of aging is that it is a consequence of a race to the bottom in terms of competition for early life reproductive success. The result is mechanisms and systems that aid early fitness at the cost of later dysfunction - and consequent aging and death. This is known as the antagonistic pleiotropy hypothesis. So we exist, do pretty well at the outset of life, but are equipped with a biochemistry that is incapable of repairing itself well enough for the long term. Some metabolic byproducts cannot be broken down, and accumulate to cause issues. The adaptive immune system must store information, and eventually runs out of capacity. And so on.
There are other minority viewpoints on the evolution of aging, numerous varieties of the programmed aging hypothesis. In this view, degenerative aging is directly selected rather than a side-effect. It is in some way advantageous to fitness. Looking at today's research materials, the variety of programmed aging hypothesis that springs to mind is the one invoking group selection: aging exists to control the population so that ecosystem collapse is avoided. Speaking generally, group selection is not well regarded, and not thought a valid mechanism of evolution. But are there circumstances in which researchers believe that group selection could be involved in the evolution of aging? The example here is a collection of organisms that are all clones of one another - such as microbes, or some lower animals such as nematodes.
Some worms programmed to die early for sake of colony
Evolutionary theorists originally believed that ageing evolved to reduce the population in order to increase food availability for the young, but scientists have since shown this cannot be true for most animal species as longer-lived non-altruists would usually be favoured by natural selection. However, certain organisms possess what appear to be self-destruct programmes, preventing them from living beyond a certain age. For example, in the tiny roundworm C. elegans, mutations to particular genes can massively increase their lifespan (from two to three weeks under laboratory conditions, to close to 20 weeks), presumably by switching off the life-shortening programme.
Researchers investigated the specifics of the C. elegans life cycle to understand why programmed death may work for them, by devising computer models of a C. elegans colony growing on a limited food supply. They tested whether a shorter lifespan would increase the reproductive capacity of colonies, by generating the equivalent of colony seeds (a dispersal form of worm called a dauer). They found that shorter lifespan, as well as shorter reproductive span and reduced adult feeding rate, increased the reproductive success of the colony.
"Our findings are consistent with the old theory that ageing is beneficial in one way, as they show how increasing food availability for your relatives by dying early can be a winning strategy, which we call consumer sacrifice. But adaptive death can only evolve under certain special conditions where populations of closely related individuals don't mix with non-relatives. So this is not predicted to apply to humans, but it seems to happen a lot in colonial microorganisms."
Shorter life and reduced fecundity can increase colony fitness in virtual Caenorhabditis elegans
In the nematode Caenorhabditis elegans, loss of function of many genes leads to increases in lifespan, sometimes of a very large magnitude. Could this reflect the occurrence of programmed death that, like apoptosis of cells, promotes fitness? The notion that programmed death evolves as a mechanism to remove worn out, old individuals in order to increase food availability for kin is not supported by classic evolutionary theory for most species. However, it may apply in organisms with colonies of closely related individuals such as C. elegans in which largely clonal populations subsist on spatially limited food patches.
Here, we ask whether food competition between nonreproductive adults and their clonal progeny could favor programmed death by using an in silico model of C. elegans. Colony fitness was estimated as yield of dauer larva propagules from a limited food patch. Simulations showed that not only shorter lifespan but also shorter reproductive span and reduced adult feeding rate can increase colony fitness, potentially by reducing futile food consumption. Early adult death was particularly beneficial when adult food consumption rate was high. These results imply that programmed, adaptive death could promote colony fitness in C. elegans through a consumer sacrifice mechanism. Thus, C. elegans lifespan may be limited not by aging in the usual sense but rather by apoptosis-like programmed death.
Potential Mechanisms to Restore Lost Function in Aged Hematopoietic Stem Cells
Hematopoietic stem cells are responsible for generating blood and immune cells. They are vital to the function of the immune system. With age their function alters in unfavorable ways, leading to the production of too great a proportion of myeloid cells versus lymphoid cells, but also declines in total. This is one of the contributing factors in the aging of the immune system, which is itself very influential of the progression of aging and age-related frailty. Thus potential ways to restore the hematopoietic stem cell population to a more youthful capacity to generate immune cells is an important part of the toolkit for human rejuvenation that lies somewhere ahead of us.
A key step in hematopoietic stem cell (HSC) aging research was achieved in 1996, revealing that HSCs from old mice were only one-quarter as efficient as those from young mice at homing to and engrafting the bone marrow (BM) of irradiated recipients. Aged HSCs are inferior to young HSCs and show incomplete reconstitution potential. This discovery established that the HSC aging process is accompanied by functional decline. Since then, differences between young and aged HSCs have been elucidated from multiple aspects, and the mechanisms of HSC aging have been gradually illustrated.
Different studies have explored the mechanisms by which aged HSC dysfunction occurs. Altered expression levels of multiple genes and mutation of some specific genes were shown to lead to HSC aging. In addition, inhibition of some signaling pathways, such as the mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways, was closely related to HSC aging. Furthermore, epigenetic perturbations also drove both cellular functional attenuation and other aging manifestations. Finally, some factors in the HSC niche, such as cytokines and enzymes, are also crucial during the aging process.
Currently, there is no doubt that HSCs show declining function during aging, but whether this dysfunction is reversible remains unclear. Notably, researchers showed that prolonged fasting can rejuvenate HSCs. Prolonged fasting reduces circulating IGF-1 levels and protein kinase A (PKA) activity in various cell populations and promotes stress resistance, self-renewal, and lineage-balanced regeneration. Further, HSC aging is accompanied by alterations in gene expression. Therefore, overexpressing knocking down the expression specific genes might be strategies to prevent HSC dysfunction. Reduced Satb1 expression was found in aged HSCs and associated with compromised lymphopoietic potential, and forced Satb1 overexpression partially restored that potential.
Aged mice exhibit increased mTOR signaling in HSCs, and mTOR inhibitor rapamycin can enhance the regenerative capacity of HSCs from aged mice, improve their immune response, and extend their life span. Cdc42 regulates diverse cellular functions, including cellular transformation, cell division, migration, enzyme activity, and cell polarity. Aged HSCs show elevated Cdc42 activity, and Cdc42 inhibition has been demonstrated to rejuvenate HSC functions. Further, inhibition of p38 MAPK reduces reactive oxygen species (ROS) levels and contributes to HSC rejuvenation. TN13, a cell-penetrating peptide-conjugated peptide, inhibited p38 activity and rejuvenated aged HSCs by reducing ROS.
One strategy to delay aging is to restore cell functions, while another is to clear senescent cells. Senescent cells accumulate with age and contribute to the development of aging-related diseases. Depletion of senescent cells mitigated irradiation-induced premature aging of the hematopoietic system and rejuvenated aged HSCs in normally aged mice.
Age-Related Changes in the Gut Microbiome and Alzheimer's Disease
Researchers here discuss potential links between (a) the detrimental changes that take place with age in the microbial populations of the gut and (b) the development of Alzheimer's disease. Given the present areas of interest in these fields of study, it seems likely that chronic inflammation is the primary point of overlap: changes in the gut microbiome promote inflammation, and inflammation drives the development of Alzheimer's.
One of the important factors that is influencing human health and attracting increasing attention of scientists during the last two decades is the gut microbiome. There are ~1,000 species and ~7,000 strains of bacteria that inhabit the human intestine, among which the most common are bacteria attributed to Firmicutes (51%) and Bacteroidetes (48%). However, over the last 15 years, the functions of the intestinal microbiome have been revised owing to the establishment of a direct link between density and species composition of the intestinal microbiome and a number of pathological conditions including diabetes, obesity, and cardiovascular diseases. These diseases, in turn, are the established risk factors for the development of Alzheimer's disease (AD), and there is data indicating that gut microbiome influences brain functions. Moreover, recent studies have revealed the significant differences in quantity and quality of gut microbiome in AD patients compared to mentally healthy individuals of the same age.
On the other hand, negative lifestyle aspects, among people living in our modern societies, are also considered important risk factors for the development of AD. The most striking result is that radical increases in Alzheimer's disease in Japan and substantial increase in developing countries are associated with changes in national diets. Furthermore, there are many undesirable lifestyle factors in the modern society that may contribute to AD development. These factors include unhealthy diet, lack of sleep, circadian rhythm disturbance, chronic noise, sedentary behavior etc., and, in turn, gut microbiome is highly sensitive to these factors. From this point of view, studying the links between modern lifestyle, gut microbiome and Alzheimer's disease is an important task that requires special attention.
Reducing the number and species diversity of many beneficial anaerobes such as Bifidobacterium and Lactobacillus, as well as a shift in the diversity of the intestinal microbiota toward pathogenic microorganisms, results in changes in local intestinal chemical and immunological parameters and induces the translocation of the gut bacteria into lymphoid tissue. These factors contribute to an increase in permeability of the intestinal barrier and blood-brain barrier and the penetration of pathological microflora and their metabolites into the brain.
On the other hand, intestinal bacteria are able to excrete functional amyloid peptides and lipopolysaccharides (LPS) in large quantities. Amyloid peptide in bacteria contributes to various physiological processes on the surface of bacterial cells, such as biofilm formation, adhesion, interaction with other bacterial and eukaryotic cells, etc. Its structure and biophysical properties are similar to human pathological amyloid. In addition to the amyloid peptide, many intestinal bacteria secrete LPS. LPS are the main components of the outer cell wall of gram-negative bacteria and, in the case of penetration from the intestinal cavity into the bloodstream, can cause neuroinflammatory reactions. Published data indicates that the LPS level in the blood plasma of patients suffering from AD is three times higher than the physiological age norm.
Heart Attack Risk is Age-Related, but Aging Also Makes Treatments Less Effective
Aging makes everything worse. Its mechanisms of damage and consequence degrade tissue function to the point of catastrophic failure, as in a heart attack. That same damage also makes the immediate consequence of a heart attack worse, and reduces regenerative capacity and the ability to respond to therapies. All in all degenerative aging is an unpleasant business, lacking an upside. The right way forward is to periodically repair the damage before it reaches a pathological level, rather than working on ways to mitigate the consequences of a sizable burden of damage.
Aging elevates the susceptibility of the heart to ischemia and myocardial infarction (MI): over 50% of ischemic heart diseases occur in people older than 70s. Cardiac contractility declines suddenly in post-ischemia infarction, which can induce heart failure and even cause death. The EF and FS drop significantly in response to cardiac stress in advanced age, which is implicated by the progressive degeneration and reduction in cardiac myocytes. Beside changes in cellular level, a number of molecular alternation contribute to age related stress intolerance, including Ca2+ handling impairment, mitochondrial dysfunction, free radical accumulation, and alteration of myosin protein expression. Recently, the crucial role of epigenetic alteration in the cardiac aging process has attracted much attention.
The therapeutic effect of ischemic cardiac dysfunction varies in old patients. Patients older than 80 have worse survival rate than 70-year-old patients after cardiac ischemic therapy, but the survival rate for patients who undergo coronary artery bypass grafting is not affected by age. Early intervention for aging patients with ischemic heart disease will decrease the mortality rate. The difference in therapeutic effects between the aged and young groups also existed following cell therapies. Aged mice with cardiac injuries that underwent cardiosphere-derived cell (CDCs) transplantation showed no improvement in cardiac function, while cardiac function was improved in the young.
Furthermore, the results of cardiac regeneration therapy for aging people is still in a matter of debate. The effectiveness of stem cell therapies is always influenced by aging-related environmental changes. For example, ageing-induced low grade systematic inflammation cause poor survival rate of injected stem cells. Similarly, stem cell-derived exosome therapies are also largely limited by recipient cell senescence which causes a deteriorated cell proliferation ability and a weaken cardiac myocyte performance.
Chronic Kidney Disease Accelerates Many Aspects of Aging, Such as Cardiovascular Disease Risk
Chronic kidney disease is an unpleasant condition. There is little that can be done for patients at the present time, though there is hope that senolytic drugs might be able to turn back the fibrosis characteristic of the condition. The kidneys are important to the correct function of tissues throughout the body, and consequently chronic kidney disease accelerates the degenerative aging of many other organs, including the cardiovascular system and brain. Finding ways to restore kidney function in older patients would be a big deal.
Chronic kidney disease (CKD) is a systemic pathology that affects approximately 10% of the population. The prevalence of CKD has increased markedly over the past decades due to aging of the population worldwide and increase in incidence of diabetes mellitus, which has become the primary cause of CKD. Nowadays, CKD is considered a public health problem that causes high rates of mortality in the population due to the association with cardiovascular diseases (CVDs). Multiple studies support the notion that patients with renal disease suffer accelerated aging, which precipitates the appearance of pathologies, including CVDs, usually associated with advanced age.
Considerable efforts have been made to slow the progression of the disease and improve the quality of life in patients with CKD. New pharmacological strategies do slow the progression of CVDs, and reduce the morbidity and mortality of CKD patients. Likewise, methods of renal replacement therapy currently offer increased purification capacity and reduced adverse effects. However, the development of CVDs in patients with CKD has not yet been halted. This may be because when CKD is diagnosed, vascular pathology is already advanced and irreversible.
The causes of vascular damage in CKD are exceptionally complex. Among the theories proposed in recent years to explain the high frequency of CVDs in renal patients, one states that senescence of peripheral blood cells (known as immunosenescence) and vascular cells (known as vascular senescence) may be involved in the initiation and perpetuation of vascular pathology that appears early in patients with CKD.
The aging process that occurs due to uremia is associated with numerous changes at the cellular and molecular level, which coincide with changes observed during the physiological aging process. These changes may explain some of the complications that typically occur in patients with CKD and CKD-associated CVDs. Expanding our understanding of the factors and molecules involved in accelerated senescence will serve to identify possible targets associated with this process. This will lead to improved methods of diagnosis and monitoring of these patients. Understanding the similarities between accelerated senescence and normal physiological aging will help establish new treatments.
Cyclin D1 as a Potential Basis for an Exercise Mimetic
Researchers continue to delve into the mechanisms by which exercise produces benefits in older individuals, with an eye to producing exercise mimetic drugs. The study here is an example of the type, comparing some of the biochemistry of exercise in young, old, exercising, and sedentary mice. This part of the field is likely to evolve in much the same way as the development of calorie restriction mimetics over the past twenty years - slowly, in other words. Cellular metabolism is very complex, and picking out target mechanisms has a fair rate of failure.
Researchers gave mice that were about 20 months old, the equivalent of being 60-70 years old in humans, and mice that were 3 to 4 months old, the equivalent of 20- to 30-year-old humans, access to an exercise wheel and allowed them to run at will. Young mice averaged about 10 kilometers each night, and the older mice covered about 5 kilometers. Two other groups of young and old mice were given wheels that didn't rotate to serve as controls.
Subsequent analysis showed that the muscle stem cells of the exercising animals remained quiescent, and that the animals did not develop significant numbers of new muscle fibers in response to the exercise. After three weeks of nightly aerobics for the active groups, the researchers compared the ability of the animals to repair muscle damage. They found that, as expected, the aged, sedentary mice were significantly less able to repair muscle damage than younger sedentary mice. However, the older animals that had exercised regularly were significantly better at repairing muscle damage than were their counterparts that did not exercise. This exercise benefit was not observed in the younger animals.
The researchers also showed that injecting blood from an old mouse that had exercised into an old mouse that hadn't conferred a similar benefit in stem cell function, suggesting that exercise simulates the production of some factors that then circulate in the blood and enhance the function of older stem cells. Further studies indicated that the exercise-induced rejuvenation observed by the researchers could be mimicked by increasing the expression of a signaling molecule called cyclin D1, which is involved in rousing resting muscle stem cells in response to damage. The discovery suggests that it may one day be possible to artificially activate this pathway to keep aging muscle stem cells functioning at their youthful best.
Indicators of Frailty Start to Appear Early, Probably Due to Lifestyle Choices
Clinicians classify frailty in a symptomatic way, looking at factors such as weight loss, weakness, walking speed, and so forth. This is a method of assessment designed for use with elderly people, but researchers here apply it to a study population that includes people in the 40-60 age range. They find that in this range, a fair number of individuals exhibit signs of what in the elderly would be called prefrailty - meaning just a few symptoms are present, rather than a majority. One logical possibility is that this is a manifestation of a sedentary, increasingly overweight population. Physical activity and good dietary choices (largely eating fewer calories) are required to minimize declines in capacity as time marches on. It requires greater neglect to be truly out of shape at age 40 as compared to age 60, but it is certainly possible to achieve.
This study reports on pre-frailty in 656 presumed healthy, independently living community-dwellers aged 40 to 75 years. We used an established frailty phenotype with two objective components (grip strength, walking speed) and three self-report measures (unintentional weight loss, physical activity, exhaustion). This phenotype was developed on people aged 65+ years and has been reported to sensitively identify pre-frailty and frailty states in this population. Our research indicates that using this frailty phenotype, pre-frailty is detectable in younger community dwellers aged 40-75 years. Moreover, neither age nor gender was significantly associated with any frailty state.
Our frailty rates (1.8% frail, 39% pre-frail, and 59.2% not frail) are comparable with those published recently from analysis of data from a large UK biobank, reporting on 493,737 people aged 37-73 years (3% frail, 38% pre-frail, and 59% not frail).
Setting unintentional weight loss aside (which requires medical investigation), our findings suggest that there are many people aged 40 years or older whose frailty status could potentially be addressed by increasing physical activity, building muscle, improving exercise tolerance, nutrition and mental health. It is reasonable to propose that chronic disease self-management and population health interventions to improve physical activity, such as workplace or community wellbeing programs, could significantly attenuate reverse or slow the onset of pre-frailty in community dwellers aged 40 years or more, and their subsequent risk of progression to frailty.
An Update on Oisin Biotechnologies and OncoSenX
This short interview with Gary Hudson of Oisin Biotechnologies (and more recently Turn.bio) covers some of the history and the present status of the company and its spinoff OncoSenX. Oisin Biotechnologies is one of the more ambitious senolytics companies working on means of destroying senescent cells in old tissues in order to produce rejuvenation. The company is using a programmable gene therapy approach rather than the small molecule development that the majority of other programs are undertaking.
"As we all know, the dilemma faced by any company that wishes to attack aging as a disease is that the FDA doesn't yet accept that premise, and requires biotechs to identify an indication - a specific disease - to be treated by any new investigational drug. While we can accommodate the FDA rules by picking a specific indication, the normal pressures of business will inevitably require that whatever indication is first chosen will dictate the path for the company into the far future. An aging-focused start-up will thus become a cancer or heart or kidney disease company, and lose its ability to attack the basis for most age-associated maladies. I wanted to avoid that trap at all costs."
This led to a model where Oisín is the platform company, providing the technology to use its unique DNA-plasmid and nanoparticle approach to kill cells based on their internal state. "Once the platform is proven scientifically and pre-clinically demonstrated, our plan was that Oisín would spin out specific indications or classes of indications, either via a conventional out-license to other biotechs or big pharmas, or as partially or wholly-owned subsidiary ventures. The oncology spinout, OncoSenX, is an example of this. In this way, Oisín controls the platform technology and manufactures the therapeutics to maintain quality control, while following the FDA-mandated path to clinical for new drugs. Additionally, since some investors will be more comfortable with conventional indication-focused ventures, this model opens up new avenues for funding, partnerships and collaborations with other companies, broadening the market appeal of our technology."""We've raised over 8m to date for both Oisín and OncoSenX, and are currently in the process of raising new funding rounds. Oisín has a Series Seed round underway for up to 5m while OncoSenX is raising a Series A of up to 30m. Oisín's funding will be used for additional preclinical studies prior to an IND for an aging-related disease indication while OncoSenX's will be used for the Phase 1 and 2 oncology trials in humans." The company's next goal is to conduct a pre-clinical trial application meeting for OncoSenX to clear the path to a Phase 1 safety and efficacy trial against human solid tumors to be conducted in Canada within a year.
The Importance of Mitophagy in Aging
Mitochondria are bacterial-like cell components, hundreds of them in each cell working to create the adenosine triphosphate (ATP) energy store molecule used to power cellular processes. Mitochondria are dynamic structures, and constantly fuse together, split apart, and replicate like bacteria. Worn mitochondria are removed on a regular basis by the cellular quality control mechanism of mitophagy, a specialized form of autophagy. The survivors replicate to make up the losses.
With advancing age, mitochondrial dynamics shift to favor fusion over fission, producing larger structures that are resilient to mitophagy. The processes of mitophagy (and autophagy in general) are also thought to decline in efficiency for other reasons. This leads to the accumulation of malfunctioning, worn, broken mitochondria in cells throughout the body, and a consequent loss of cell function and tissue function. This is most likely an important component of degenerative aging, and thus restoration of mitophagy and mitochondrial function are important goals in the field of rejuvenation research.
Mitochondria are important for cellular life and death, implying that mitochondrial homeostasis must be tightly controlled and fine-tuned when cells respond to stress. Mitophagy is the primordial mechanisms for mitochondrial quality and quantity control and multiple mechanisms control this process. Some studies indicate an ample crosstalk between different mitophagy pathways that may coordinate and complement to deal with environmental challenges.
Exercise has long been known to promote healthy aging and decrease the susceptibility to age-related diseases probably, depending on the induction of autophagy. Mitophagy may also be involved in the beneficial effects of exercise. A recent study has shown that exercise activates the AMPK-ULK1 cascade to provoke the removal of damaged mitochondria via mitophagy. Caloric restriction is yet another way to extend healthy lifespan. Similar to exercise, nutrient deprivation activates the AMPK-ULK1 cascade that is required for mitophagy to remove damaged mitochondria and promote cellular survival.
Some compounds exert their lifespan extending effect via mitophagy. Thus, urolithin A extends lifespan and improves fitness during C. elegans aging and improves muscle function and exercise capacity in rodents. In-depth analysis demonstrates that mitophagy is required for the beneficial effect of urolithin A. Nicotinamide adenine dinucleotide (NAD) levels decrease with age, while the upregulation or replenishment of NAD metabolism has been shown to exhibit beneficial effects against aging and age-associated diseases. Treatments that increase intracellular NAD+ improve mitochondrial quality via mitophagy. Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), prolongs life in yeast, worms, flies, and mice. Recent studies indicate that eliminating damaged mitochondria via mitophagy may be one of the mechanisms responsible for the beneficial effects of rapamycin.
In conclusion, dysfunction of mitochondria is one of the major characteristics of aging and age-related disease. Increasing evidence shows that mitophagy (by removing damaged mitochondria) is significantly involved in counterbalancing age-related pathological conditions. Thus, chronic stimulation of mitochondrial turnover by enhancing mitophagy is a promising approach to delay age-related diseases and to extend healthspan and lifespan.
GDF11 in the Regeneration and Aging of Skin
GDF11 was identified in parabiosis studies as beneficially influencing stem cell and tissue function. Levels of GDF11 decline with age. There was some debate over whether or not the early research was correct, but GDF11 is presently in clinical development as a basis for regenerative therapies for the old. Researchers here outline a role of GDF11 in the regeneration and tissue maintenance of skin, focusing on its anti-inflammatory role. The chronic inflammation of aging is present in all tissues, skin included, and is detrimental to health and tissue function. Anti-inflammatory effects are likely important in the observed benefits from upregulation of GDF11 in old animals.
GDF11 regulates essential cell differentiation and proliferation responses and is expressed in numerous tissues, including the skin, heart, skeletal muscle, and developing nervous system. Its expression is at the highest level in young adult organs and seems to decline during aging. Some studies have shown that GDF11 can reverse age-related dysfunction in muscle, nervous and cardiovascular systems. Although serum GDF11 levels were found to be decreased in old mice, supplementation with GDF11 "rejuvenated" them, thereby suggesting that GDF11 is a key player in mammalian life span. It has also been suggested that GDF11 is involved in the age-related global physiological decline in function, and that restoring circulating blood levels of GDF11 could reverse some of the cellular and physiological dysfunctions observed in aged mice.
Tumor necrosis factor-α (TNF-α) plays a key role in inflammatory diseases, including skin inflammation, while GDF11 inhibits inflammatory reactions. GDF11 treatment antagonizes TNF-α-induced inflammation in macrophages, and the administration of GDF11 appears to attenuate skin inflammation. Studies show that TNF-α-induced activation of the nuclear factor kappa B (NF-κB) signaling pathway, which is known to participate in various inflammatory conditions, is limited by GDF11 treatment.
Heat shock proteins (HSPs) are molecular chaperones essential for the maintenance of cellular functions, but they can be released extracellularly upon cellular injury or necrosis. GDF11 induces protective effects in various tissues through the suppression of oxidative stress and the expression of HSPs. As the key member of the TGF-β superfamily, GDF11 represents a promising therapeutic agent for the treatment of a number of inflammatory skin diseases, including psoriasis.
A Cardiac Patch Without Cells Improves Regeneration Following Heart Attack
It is a sad truth that near all transplanted cells in near all cell therapies die quickly, and do not integrate with tissues to improve function. The benefits that do occur result from the signals secreted by the transplanted cells before they die. The research community has been undertaking a range of strategies to address this issue. One is to produce a scaffold material that mimics tissue sufficiently well to give cells the support they need to survive, populate it with suitable cells, and then transplant the resulting structure. This can produce 10% survival of transplanted cells, an enormous improvement over delivery of cells alone.
One manifestation of this approach is a heart patch, a thin structure that is placed onto the surface of an injured heart. Heart patches have performed fairly well to date in the lab, but like all tissue engineering work, that they use cells makes them logistically challenging and expensive to deploy. Researchers here report on how well a patch works if the cells are left out of the equation: just transplant the scaffold, a structure that can be mass manufactured and stored comparatively easily, and see whether it encourages native cells to greater regeneration.
Cardiac patches are being studied as a promising future option for delivering cell therapy directly to the site of heart attack injury. However, current cardiac patches are fragile, costly, time-consuming to prepare and, since they use live cellular material, increase risks of tumor formation and arrhythmia.
"We have developed an artificial cardiac patch that can potentially solve the problems associated with using live cells, yet still deliver effective cell therapy to the site of injury." Researchers built the patch by first creating a scaffolding matrix from decellularized pig cardiac tissue. Synthetic cardiac stromal cells - made of a biodegradable polymer containing cardiac stromal cell-derived repair factors - were embedded in the matrix. The resulting patch contained all of the therapeutics secreted by the cells, without live cells that could trigger a patient's immune response.
In a rat model of heart attack, treatment with the artificial cardiac patch resulted in ~50% improvement of cardiac function over a three-week period compared to non-treatment, as well as a ~30% reduction in scarring at the injury site. The researchers also conducted a seven-day pilot study of heart attack in a pig model, and saw ~30% reduction in scarring in some regions of the pig hearts, as well as stabilized heart function, compared to non-treatment. Additional experiments demonstrated that artificial patches that had been frozen were equally potent to freshly created patches.