Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Chaperone Mediated Autophagy as a Target for the Treatment of Atherosclerosis
- An Enhanced Natural Killer Cell Therapy Clears Senescent Cells in Mice
- More on the Safe Mitochondrial Uncoupling Compound BAM15
- Towards Improved Partial Reprogramming Techniques as a Basis for Rejuvenation Therapies
- S-adenosyl-L-homocysteine Supplementation as a Methionine Restriction Mimetic Strategy
- SENS Research Foundation is Expanding
- Systematic Screening of Cell Death Pathways in Search of New Senolytics
- Evidence for a Mechanism that Operates in Oocytes to Reduce Mitochondrial DNA Mutation Rate
- More Mitochondrial Fission Improves Mitophagy, Mitochondrial Function, and Angiogenesis
- Mitochondrially Targeted Tamoxifen as a Senolytic Drug
- Envisaging Alzheimer's Disease as Innate Autoimmunity
- Bacteria Promote Cancer Metastasis
- The Lipid Invasion Model of Alzheimer's Disease
- Small Molecules to Provoke Regrowth of Hair Cells in the Inner Ear
- Dopaminergenic Neurons Regulate Longevity in Flies
Chaperone Mediated Autophagy as a Target for the Treatment of Atherosclerosis
Forms of autophagy function to remove unwanted, excess, or damaged structures and other molecules in the cell. These materials are delivered to a lysosome, a membrane packed with enzymes capable of dismantling near every macromolecule a cell will encounter, producing raw materials for reuse. Autophagy is quite clearly connected to tissue function and aging in a number of ways. It appears to decline in quality with age, leading to downstream problems in cell and tissue function as worn and damaged component parts accumulate. Upregulation of autophagy for long periods of time is a feature of numerous interventions, such as calorie restriction and calorie restriction mimetics, that result in slowed aging.
In today's research materials, the team involved in developing autophagy-upregulating small molecule therapies at Life Biosciences discuss evidence for chaperone-mediated autophagy to be relevant in atherosclerosis. In atherosclerosis, fatty deposits build up in blood vessels as a result of macrophages becoming less capable of returning excess cholesterol to the blood stream. The chronic inflammation and oxidative stress of age disrupts the ability of macrophages sufficiently to allow atherosclerotic plaques to form in the first place, but once formed the plaque is a hostile environment that overwhelms macrophages with excess cholesterol.
Anything that improves macrophage resilience can help. It is actually not that hard to significantly slow the growth of atherosclerotic plaque in mice, and many methods work well. Small differences sustained over time add up. Reversal of atherosclerosis is a much harder problem, and the work involving increased autophagy noted here is not a demonstration of reversal, but rather just another demonstration of slowed atherosclerosis. In that sense, it is not that exciting; it is on a par with what can be done with drugs like statins that lower blood cholesterol. Lower blood cholesterol over a lifetime can halve the risk of dying due to atherosclerosis in humans, but statins as a treatment applied in old age are nowhere near that good at reducing cardiovascular mortality.
Researchers Find New Strategy for Preventing Clogged Arteries
Chaperone-mediated autophagy (CMA) keeps cells functioning normally by selectively degrading the many proteins that cells contain. In CMA, specialized chaperone proteins bind to proteins in the cytoplasm and guide them to enzyme-filled cellular structures called lysosomes to be digested and recycled. Disrupted CMA allows damaged proteins to accumulate to toxic levels, contributing to aging and - when the toxic buildup occurs in nerve cells - to neurodegenerative diseases including Parkinson's, Alzheimer's, and Huntington's disease.
To investigate CMA's role in atherosclerosis, researchers promoted atherosclerosis in mice by feeding them a fatty Western diet for 12 weeks and monitoring CMA activity in plaque-affected aortas of the animals. CMA activity initially increased in response to the dietary challenge; after 12 weeks, however, plaque buildup was significant, and virtually no CMA activity could be detected in the two types of cells - macrophages and arterial smooth muscle cells - that are known to malfunction in atherosclerosis, leading to the buildup of plaque within arteries. Feeding the high-fat diet to mice totally lacking in CMA activity produced even stronger evidence of CMA's importance: plaques nearly 40% larger than those in control animals that were also on the high-fat diet.
The researchers genetically "upregulated" CMA in mice that were fed a pro-atherosclerotic, high-fat Western diet and later compared them with control mice fed the same diet for 12 weeks. The CMA-boosted mice had greatly improved blood lipid profiles, with markedly reduced levels of cholesterol compared with the control mice. Plaque lesions that formed in the genetically altered mice were significantly smaller and milder in severity compared with plaques in control mice.
Protective role of chaperone-mediated autophagy against atherosclerosis
Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to pro-atherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression.
An Enhanced Natural Killer Cell Therapy Clears Senescent Cells in Mice
A growing burden of senescent cells in tissues throughout the body is an important contributing cause of degenerative aging. These cells secrete pro-growth, pro-inflammatory signals that, when maintained for the long term, are highly disruptive of cell and tissue function. Cellular senescence is an important contributing cause in many age-related conditions. Senescent cells are created constantly throughout life, and the immune system is responsible for removing those that fail to destroy themselves. Unfortunately, it becomes worse at this task with age.
Natural killer cells are one of the immune cell populations involved in senescent cell clearance, and researchers are interested in ways to enhance this ability. One possibility is to increase the number of natural killer cells present in the body. In today's open access paper, rsearchers here show that providing additional natural killer cells in the form of a cell therapy can reduce the burden of senescent cells in mice. They additionally propose ways to enhance the ability of transplanted cells to clear lingering senescent cells.
Combining adoptive NK cell infusion with a dopamine-releasing peptide reduces senescent cells in aged mice
Senescent cells (SNCs) can be recognized and removed by the immune system. Previous studies have shown that SNCs activate natural killer (NK) cells by up regulating the major histocompability class I chain-related protein A and B activating ligand. However, with increasing age, the efficiency of the immune system decreases, which can lead to the immune escape of SNCs. Methods to overcome immune escape caused by decreased immune function have been explored in cancer therapy. Recent progress has been made in adoptively transferring NK cells to eliminate tumours, which has shown some efficacy; thus, it was reasonable to assume that the adoptive infusion of NK cells might produce cytotoxicity in SNCs.
The nervous and immune systems are the two most important adaptive systems of the body. Several studies have shown that dopamine (DA) as an immune regulator is a key to the neuroimmune communication. DA performs its biological functions by interaction with and activation of dopamine receptors (DR), which are divided into 2 subgroups, D1-like (D1 and D5), and D2-like (D2, D3, and D4). In terms of their different functions, the engagement of D1-like DR stimulates cAMP production, while the engagement of D2-like DR inhibits cAMP production. Previous studies have shown that D1-like DR stimulation enhances the cytotoxicity of NK cells both in vitro and in vivo. However, DA levels drop as human age increase. Thus, we hypothesized that dopaminergic drugs could enhance cytotoxicity of the adoptive infusion of NK cells.
Here, we propose the use of the nonapeptide Acein, which interacted with angiotensin converting enzyme (ACE I) to induce DA secretion, in combination with systemic NK cell therapy to eliminate SNCs. In vitro results showed that NK cells removed SNCs, independently of senescence inducers and cell types. In an aging mouse model, NK cell therapy in combination with Acein significantly reduced the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells in multiple tissues, decreased the expression of senescence-associated genes in major organs, and alleviated senescence-associated secretory phenotypes (SASPs). The results of this study provide insights into possible restoration of the immune surveillance of chronic SNCs using NK cell therapy in combination with Acein.
More on the Safe Mitochondrial Uncoupling Compound BAM15
Mitochondrial uncoupling is a mechanism by which mammals maintain body temperature. It diverts the activity of the hundreds of mitochondria present in every cell from production of the chemical energy store molecule adenosine triphosphate (ATP), used to power cellular processes, to the production of heat. Additional mitochondrial uncoupling, above and beyond that which occurs naturally, produces beneficial effects on long term health, as is true of a range of manipulations that influence mitochondrial function. In this case, however, it doesn't appear to slow aging, even while resulting in desirable outcomes such as a reduction in visceral fat tissue.
Mild additional mitochondrial uncoupling is a good thing. Excessive mitochondrial uncoupling can produce severe side-effects and death, however, and that makes it a tricky process to produce drugs targeting this mechanism. One of the world's more dangerous and interesting drugs is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP). In addition to being an explosive compound, it stays in the body long enough to make it all too easy to slip from a safe dose to potentially fatal dose. It is thus no longer used, after a period of interest as a weight loss treatment many decades ago.
The effects of mitochondrial uncoupling on long term health are interesting enough, in this era of widespread obesity, for the research community to have worked towards safe mitochondrial uncoupling compounds. One of these, BAM15, is the subject of today's research materials. You may recall that this line of work was discussed here a few years ago. There is progress towards a potential path to the clinic, but only slowly, as is usually the case.
Chemical Compound Promotes Healthy Aging
Researchers have provided the first evidence that BAM15, a mitochondrial uncoupler, prevents sarcopenic obesity, or age-related muscle loss accompanied by an increase in fat tissue. The weakness and frailty common to sarcopenic obesity are offset in older mice - the equivalent of aged 60-65 in human years - given BAM15. The mice, all of whom had obesity, were fed high-fat diets. Despite that, the mice given BAM15 lost weight and got stronger and more active. "In this study, the aged mice increased their muscle mass by an average of 8 percent, their strength by 40 percent, while they lost more than 20 percent of their fat."
BAM15 improves many of the key determinants of health and aging, including: (a) removing damaged mitochondria, the power plants of the cell; (b) making more healthy mitochondria, and; (c) reducing "inflammaging," or age-related inflammation, linked to muscle loss.
Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control
Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.
BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g) which was attributable to increased energy expenditure. BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g), and locomotor activity. Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation, enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control, increased mitochondrial activity, restricted endoplasmic reticulum (ER) misfolding, while limiting ER stress, apoptotic signalling, and muscle protein degradation.
Towards Improved Partial Reprogramming Techniques as a Basis for Rejuvenation Therapies
Partial reprogramming involves exposing cells to the Yamanaka factors capable of turning somatic cells into induced pluripotent stem cells, but not for so long as to result in that transformation. The initial stage of reprogramming, prior to transformation into stem cells, in which epigenetic marks are reset to a youthful configuration, is the desirable outcome. This results in rejuvenation of cell function, as protein production and the operation of cellular processes return to that of youth. This cannot repair DNA damage, and will probably help little with problems relating to persistent metabolic waste in long-lived cells, but the evidence from animal studies suggests that partial reprogramming can be beneficial enough to form the basis for a true rejuvenation therapy.
Partial reprogramming is a relatively new line of research and development, through very well funded of late. Numerous biotech companies are working towards the production of therapies based upon partial reprogramming techniques. These are first generation efforts, however, and the research community will inevitably improve upon the protocols of partial reprogramming, even as the first commercial efforts move towards the clinic. Today's research materials are an example of the sort of work taking place in this part of the field: attempts to optimize partial reprogramming in cell culture, alongside better measurements of the degree to which benefits to cell function are produced.
A jump through time - new technique rewinds the age of skin cells by 30 years
The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called 'maturation phase transient reprogramming', exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.
Researchers looked at multiple measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age. The second is the transcriptome, all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets. "Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work."
Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first 'maturation phase transient reprogramming' (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction.
Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cell attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent.
The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.
S-adenosyl-L-homocysteine Supplementation as a Methionine Restriction Mimetic Strategy
Methionine restriction produces benefits to health and longevity in animal studies. This involves minimizing the dietary intake of the essential amino acid methionine while maintaining all of the other necessary nutrients. Much of the nutrient sensing that alters downstream cellular activities in response to a lower intake of calories is based upon assessment of methionine levels. Thus methionine restriction without calorie restriction triggers a sizable fraction of the same beneficial upregulation of cell maintenance processes, leading to improved tissue function, slowed aging, and so forth.
In comparison to the practice of calorie restriction, achieving a meaningful degree of methionine restriction, without reducing calories, is a harder dietary undertaking. The publicly available data on methionine levels is of poor quality and far from complete. Near all staple food choices contain a lot of methionine. There are medical diets manufactured with low methionine levels, used to treat a few uncommon conditions, but they are neither easily obtained nor easily reverse engineered. These issues could be bypassed given a suitable venture focused on manufacturing such a diet for the public rather than for patients, but it is unclear that producing low methionine foods outside the medical diet industry is in any way commercially viable.
Thus we come to whether or not methionine-based nutrient sensing can be triggered by other means. In today's open access paper, researchers take a look at one of the options on the table. Memetics will never be as good as the real thing, but it is in principle possible that any given mimetic could be good enough to merit time and effort on the part of the research community. Certainly, the quality of calorie restriction mimetics varies widely, and we might expect the same to be true of methionine restriction mimetics.
S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects
Dietary restriction, including methionine restriction (MetR) , is an effective strategy for promoting longevity and counteracting age-related morbidities. In addition, genetic manipulation or pharmacological inhibition of methionine (Met) metabolic pathways and a Met-restricted diet prolong lifespan. Several studies indicate that a MetR diet is possible for humans, but long-term compliance to such a diet is considered problematic. Previously, we showed that a yeast mutant that accumulates S-adenosyl-L-methionine (SAM) to high levels exhibited reduced intracellular Met and lifespan extension mediated through AMPK activation. We also showed that in a wild-type (WT) strain, supplementation with S-adenosyl-L-homocysteine (SAH) increased SAM levels, activating AMPK, and extending lifespan.
To investigate the basis for SAH-mediated longevity, we performed metabolomics analysis of a WT yeast strain. As previously reported, SAH administration increased levels of SAH and SAM, a methyl group donor. SAH is a potent competitive inhibitor of SAM-dependent methyltransferases, and SAH accumulation thereby impairs cell growth. we speculate that SAH supplementation can increase SAM synthesis through an unknown mechanism. Since SAM synthesis requires Met, stimulating SAM production can decrease the quantity of intracellular Met. Notably, among the amino acids, Met exhibited significantly reduced levels after SAH supplementation.
The lower Met content in SAH-treated cells suggests that longevity from SAH supplementation can induce a MetR state. Hence, since MetR extends chronological lifespan (CLS) in an autophagy-dependent manner, we investigated the effect of SAH on autophagy. SAH treatment increased degradation of an autophagy marker, suggesting that SAH administration promotes autophagy.
Subsequently, to determine whether SAH acts as an anti-aging metabolite in a metazoan, we investigated its effects on the nematode C. elegans. SAH treatment extended the lifespan of WT animals in a concentration-dependent manner,. Notably, SAH did not affect food consumption, brood size, or viability. SAH also partially prevented the aging-associated decrease in physical capacity. Altogether, these results suggest that SAH mediates phylogenetically conserved anti-aging effects.
In conclusion, our results suggest that SAH extends lifespan by inducing MetR or mimicking its downstream effects. Since the lifespan-extending effects of SAH are conserved in yeast and nematodes, and MetR extends the lifespan of many species, exposure to SAH is expected to have multiple benefits across evolutionary boundaries. Our findings offer the enticing possibility that in humans the benefits of a MetR diet can be achieved by promoting Met reduction with SAH. The use of endogenous metabolites, such as SAH, is considered safer than drugs and other substances, suggesting that it may be one of the most feasible ways to prevent age-related diseases.
SENS Research Foundation is Expanding
The non-profit SENS Research Foundation is expanding their research center in the Bay Area. A number of interesting projects relevant to human rejuvenation are underway at their facility, such as work on allotopic expression of mitochondrial genes. This follows a sizable increase in funding last year, arriving from the cryptocurrency community. One of the more interesting and perhaps less visible consequences of the use of blockchains to create cryptocurrencies is a concentration of wealth in the hands of comparatively young, comparatively visionary people who are willing to try to change the world, such as by, for example, funding high risk, high reward projects in medical research and development.
We are thrilled to announce the expansion of the SENS Research Foundation's Research Center to over 11,000 square feet with the addition of new lab and office space. This is more than doubling our current facility in Mountain View, California that is home to the foundation' global operations.
Thank you to all the donors who made this expansion possible. We are grateful beyond words for your ongoing support, as it has enabled us to rapidly expand not just our lab space, but our internal research programs, as well as the equipment and other resources needed to accelerate the defeat of age-related disease. We will host a Grand Re-Opening early this summer to which everyone will be invited - watch your inbox and stay tuned for details.
Systematic Screening of Cell Death Pathways in Search of New Senolytics
Senolytic drugs capable of clearing senescent cells from the bodies of older people will be a very important part of the medicine of tomorrow. A burden of senescent cells contributes significantly to aging, and removing them produces quite rapid and profound rejuvenation in animal models. If taking the small molecule drug approach, a diversity of senolytics will likely be needed in order to clear most senescent cells from most tissues, due to differences in drug biodistribution and biochemistry of senescence between tissue types. The search for new senolytic drug targets and drug compounds has been underway in earnest for a few years, and researchers are starting to become more rigorous and systematic, as demonstrated here.
Selectively ablating senescent cells ("senolysis") is an evolving therapeutic approach for age-related diseases. Current senolytics are limited to local administration by potency and side effects. While genetic screens could identify senolytics, current screens are underpowered for identifying genes that regulate cell death due to limitations in screen methodology.
Here, we establish Death-seq, a positive selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263, a BH3 mimetic. SMAC mimetics, enhancers of cell death in our screens, synergize with ABT-199, another BH3 mimetic that is not senolytic alone, clearing senescent cells in models of age-related disease while sparing human platelets, avoiding the thrombocytopenia associated with ABT-263.
In summary, Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identify drug targets for diverse pathological states such as senescence, cancer, and neurodegeneration.
Evidence for a Mechanism that Operates in Oocytes to Reduce Mitochondrial DNA Mutation Rate
Researchers here show that, in primates, oocyte cells are more protected from mutations to mitochondrial DNA in later life. This suggests that one or more mechanisms are operating to produce this outcome. Given that mitochondrial DNA mutations are implicated in age-related loss of mitochondrial function and other aspects of aging, the existence of protective mechanisms is potentially interesting. It is not as interesting as the ability to repair or replace damaged mitochondrial DNA, of course. Mechanisms that can only produce sizable differences by operating over long periods of time are a poor foundation upon which to build rejuvenation therapies.
New mutations occur at increasing rates in the mitochondrial genomes of developing egg cells in aging rhesus monkeys, but the increases appear to plateau at a certain age and are not as large as those seen in non-reproductive cells, like muscle and liver. A new study using an accurate DNA sequencing methodology suggests that there may be a protective mechanism that keeps the mutation rate in reproductive cells relatively lower compared to other tissues in primates, a fact that could be related to the primate - and therefore human - propensity to reproduce at later ages.
Mitochondria are cellular organelles - often called the powerhouse of the cell because of their role in energy production - that have a genome of their own separate from the cell's nuclear genome. Researchers sequenced the mitochondrial genome from muscle cells, liver cells, and oocytes - precursor cells in the ovary that can become egg cells - in rhesus macaques that ranged in age from one to 23 years. This age range covers almost the entire reproductive lifespan of the monkeys. Tissues for the study were collected opportunistically over the course of several years from primate research centers when animals died of natural causes or were sacrificed because of diseases not related to reproduction. Oocytes, and not sperm cells, were used because mitochondria are inherited exclusively through the maternal line.
Overall, the researchers saw an increase in the mutation frequency in all of the tested tissues as the macaques aged. Liver cells experienced the most dramatic change with a 3.5-fold increase in mutation frequency over approximately 20 years. The mutation frequency in muscle increased 2.8-fold over the same time span. The mutation frequency in oocytes increased by 2.5-fold up to age nine, at which point it remained steady. Our results suggest that primate oocytes might have a mechanism to protect or repair their mitochondrial DNA, an adaptation that helps to allow later reproduction. The precise mechanism leading to the plateau in mutation frequency in oocytes remains enigmatic, but it might act at the level of elimination of defective mitochondria or oocytes."
More Mitochondrial Fission Improves Mitophagy, Mitochondrial Function, and Angiogenesis
Mitochondria are essential cell components that become dysfunctional with age, a cause of a significant fraction of age-related degeneration. These organelles are descended from ancient symbiotic bacteria, and the herd of mitochondria in a cell is dynamic, fusing together, splitting apart, and passing around component parts. As mitochondria become worn and damaged, they are removed by the quality control process of mitophagy. This all works well in youth.
In the context of aging, a fair amount of evidence points to impaired mitochondrial fission as an important contributing cause of impaired mitophagy, which in turn leads to impaired mitochondrial function as damaged mitochondria accumulate, which in turn causes all sorts of issues. The issue in question here is the reduced generation of new blood vessels with age, an impairment that may be very significant, as it contributes to the decline of capillary networks throughout the body and reduced blood supply to energy-hungry organs such as muscles and the brain.
The protein Drp1 is best known to enable an orderly splitting, or fission, of mitochondria so that one becomes two and/or mitophagy, which is trimming off dysfunctional parts of existing mitochondria and helping eliminate mitochondria that are beyond repair. Researchers now have early evidence that when oxygen levels are low in common problems like heart disease and peripheral artery disease in the legs, Drp1 gets modified and a new job. It again promotes splitting, or fission, of the powerhouses but in this case, the magic is in generating a powerful signal, via creation of reactive oxygen species (ROS), that makes glycolysis happen. Ready energy like from glycolysis is needed for the cell proliferation, migration, and movement of angiogenesis, and the endothelial cells that line existing blood vessels take the lead in making new ones.
Hypoxia, like the heart muscle crying out for more oxygen, is the natural cue for angiogenesis. Vascular endothelial growth factor (VEGF), which does just what its name implies, outside the endothelial cell is naturally stimulated by hypoxia, then in turn activates NADPH oxidase, a family of enzymes that generate ROS - in this case the kind that enables cell signaling. ROS generated by the mitochondria in turn activates AMPK, an enzyme key to regulating energy levels in cells and known to use glucose to quickly generate sufficient energy to support important biological work like making new blood vessels.
When ROS from the mitochondria is blocked, angiogenesis produced by endothelial cells also is impaired. And it appears to be a two-way street because VEGF's ability to enable angiogenesis also is impaired, and mitochondrial ROS can activate NADPH oxidase ROS and vice versa. Together the result is sustained signaling. If you block mitochondrial ROS, the chain reaction is blocked.
Mitochondrially Targeted Tamoxifen as a Senolytic Drug
Researchers here note that mitochondrially targeted tamoxifen, developed as a cancer therapeutic, is sufficiently senolytic to treat conditions in which senescent cells play a significant role. They have chosen to target type 2 diabetes, a case of following the money given the present epidemic of obesity. It is actually quite surprising that few of the groups developing novel senolytic drugs have set their sights on diabetes, given the solid evidence of the past few years for the pathology of both type 1 diabetes and type 2 diabetes to be mediated in large part by cellular senescence.
Senescent cells play an important role in the induction of type 2 diabetes mellitus (T2DM) pathogenesis. Considering that metabolic and signaling changes associated with T2DM can promote senescence, senescent cells are components of the "pathogenic loop" in diabetes. In obese and diabetic mice, visceral adipose tissue (VAT) is the most prominent compartment of senescent cells accumulation. VAT, therefore, presents the nexus of mechanisms involved in longevity and age-related metabolic dysfunctions. A close relationship between visceral fat content and the risk of T2DM and cardiovascular complications has also been demonstrated in humans. Components of the senescence-associated secretory phenotype (SASP) secreted by adipose-derived senescent cells confer insulin resistance to metabolic tissues and attract immune cells that can exacerbate the effects of insulin resistance. Moreover, there is a close relationship between senescence and fat accumulation in hepatocytes followed by the development of steatosis in diabetic mice.
Senolytic agents may improve glucose control and obesity- and diabetes-related pathologies, supporting the idea that targeting senescent cells may be a promising strategy for T2DM management. Mitochondrial function is an important determinant of the aging process, and we have recently reported that targeting mitochondria in senescent cells presents a plausible way to eliminate such cells in the context of pathological senescence as well as senescence-associated diseases. Using mitochondrially targeted tamoxifen (MitoTam), our proprietary agent with anticancer activity, we have achieved specific elimination of senescent cells.
Treatment with MitoTam effectively reduces oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential in senescent cells, and severely affects mitochondrial morphology based on a low level of the ADP/ATP translocation channel ANT2 (adenine nucleotide translocase 2). These cells cannot, therefore, pump ATP inside mitochondria in order to maintain mitochondrial potential by cleavage of ATP by ATPase, resulting in the collapse of mitochondrial integrity and function18. Based on these results, we reasoned that MitoTam may present a non-cannonical therapeutic modality to treat senescence-associated pathologies, such as T2DM.
Here we show that MitoTam considerably improves glucose control, decreases body weight, and reduces diabetic markers as well as diabetic comorbidities in mice with diet-induced obesity and prediabetes. These improvements are associated not only with a reduction of food intake and a drop in the number of senescent cells in the organism but also with rejuvenation of the adipose tissue, suggesting the role of MitoTam in T2DM treatment and prevention of chronic diabetic complications.
Envisaging Alzheimer's Disease as Innate Autoimmunity
There is no shortage of theorizing in the Alzheimer's disease community. The lengthy failure of therapies targeting amyloid-β, first the failure to clear amyloid-β meaningfully, and then the failure to produce benefits in patients after clearance was achieved, has led to a great deal of frustration and the search for new views of the condition that might lead to different therapeutic strategies. Many of these viewpoints should probably be taken with a grain of salt (e.g. that modern painkillers play an important role), while others are quite compelling (e.g. persistent viral infection, or the burden of cellular senescence in supporting cells in the brain). Today's example is an interesting reframing of what is known of the role of amyloid-β in the innate immune system, and how that might apply to Alzheimer's disease.
As new potentially explanatory biochemical mechanisms for Alzheimer's disease (AD) emerge, they are often regarded as mutually exclusive and in competition - a situation resulting in pronouncements that the amyloid hypothesis, plagued by numerous clinical trial failures, is dead and needs to be replaced. However, a variety of data compellingly link amyloid beta (Aβ) to the pathogenesis of AD. Accordingly, rather than categorically rejecting the role of Aβ, the need for a new widely encompassing conceptualization of AD that unifies seemingly divergent theories into a single harmonized explanation emerges as an effective strategy. Incorporating protein misfolding mechanisms into a broader-based immunopathic model of AD could attain such a goal - a goal which can be achieved by repositioning Aβ as an immunopeptide.
In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self-perpetuating autoimmune cycle. AD thus emerges as a brain-centric autoimmune disorder of innate immunity.
Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in the human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex pathogenesis.
Bacteria Promote Cancer Metastasis
Given the onset of a particular type of cancer, why does that cancer become a much worse prospect for only some individuals? Why are some people more prone to metastasis, for example? A perhaps underappreciated factor is the interaction of infectious agents with the tumor microenvironment, as researchers discuss here. Exposure to pathogens, and particularly persistent pathogens, may be a good explanation for many areas of medicine in which only some people bearing all of the traditional risk factors go on to develop the worst outcomes.
Microbes play a critical role in affecting cancer susceptibility and tumor progression, particularly in colorectal cancers. However, emerging evidence suggests that they are also integral components of the tumor tissue itself in in a broad range of cancer types, such as pancreatic cancer, lung cancer, and breast cancer. Microbial features are linked to cancer risk, prognosis, and treatment responses, yet the biological functions of tumor-resident microbes in tumor progression remain unclear.
Whether these microbes are passengers or drivers of tumor progression has been an intriguing question. Researchers used a mouse model of breast cancer with significant amounts of bacteria inside cells, similar to human breast cancer. They found that the microbes can travel through the circulatory system with the cancer cells and play critical roles in tumor metastasis. Specifically, these passenger bacteria are able to modulate the cellular actin network and promoted cell survival against mechanical stress in circulation.
"We were surprised initially at the fact that such a low abundance of bacteria could exert such a crucial role in cancer metastasis. What is even more astonishing is that only one shot of bacteria injection into the breast tumor can cause a tumor that originally rarely metastasizes to start to metastasize. Intracellular microbiota could be a potential target for preventing metastasis in broad cancer types at an early stage, which is much better than to have to treat it later on."
The Lipid Invasion Model of Alzheimer's Disease
Researchers here discuss a model of Alzheimer's disease that is centered around consequences of the age-related disruption of the blood-brain barrier. This barrier of specialized cells lines blood vessels in the central nervous system, and acts to control the passage of cells and molecules to and from the brain. Unfortunately, it becomes leaky with age, failing just like every other system and structure in the body. The researchers propose an interesting hypothesis, but it stands as one of many new ways to look at Alzheimer's disease. A great deal of theorizing has been provoked by the ongoing failure to make progress in the development of therapies to meaningfully slow or reverse the progression of this form of neurodegeneration. It remains to be seen as to whether any of it will lead to better roads forward.
We propose a new hypothesis for Alzheimer's disease (AD) - the lipid invasion model. It argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD.
The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury. The lipid invasion model gives a new rationale for what we already know about AD, explaining its many associated risk factors and neuropathologies, including some that are less well-accounted for in other explanations of AD. It offers new insights and suggests new ways to prevent, detect, and treat this destructive disease and potentially other neurodegenerative diseases.
Small Molecules to Provoke Regrowth of Hair Cells in the Inner Ear
There is some debate over whether age-related hearing loss is a matter of loss of hair cells in the inner ear, or a loss of the connections between those cells and the brain. Since various groups are working towards hair cell regeneration, including the one noted here, this debate should be resolved not too many years from now. The easiest way to answer questions of this nature, meaning which form of biological damage is the important one in a given age-related condition, is to fix that damage and see what happens.
The biotechnology company Frequency Therapeutics is seeking to reverse hearing loss - not with hearing aids or implants, but with a new kind of regenerative therapy. The company uses small molecules to program progenitor cells, a descendant of stem cells in the inner ear, to create the tiny hair cells that allow us to hear. Hair cells die off when exposed to loud noises or drugs including certain chemotherapies and antibiotics. Frequency's drug candidate is designed to be injected into the ear to regenerate these cells within the cochlea. In clinical trials, the company has already improved people's hearing as measured by tests of speech perception - the ability to understand speech and recognize words.
The company has dosed more than 200 patients to date and has seen clinically meaningful improvements in speech perception in three separate clinical studies. Another study failed to show improvements in hearing compared to the placebo group, but the company attributes that result to flaws in the design of the trial. Now Frequency is recruiting for a 124-person trial from which preliminary results should be available early next year.
Progenitor cells reside in the inner ear and generate hair cells when humans are in utero, but they become dormant before birth and never again turn into more specialized cells such as the hair cells of the cochlea. Humans are born with about 15,000 hair cells in each cochlea. Such cells die over time and never regenerate. In 2012, the research team was able to use small molecules to turn progenitor cells into thousands of hair cells in the lab. The researchers believe their approach offers advantages over gene therapies, which may rely on extracting a patient's cells, programming them in a lab, and then delivering them to the right area.
Dopaminergenic Neurons Regulate Longevity in Flies
An interesting commentary here notes the extended life span in flies that results from the upregulation of the Mask gene in dopaminergenic neurons only. This is accompanied by extended reproductive life span as well, indicating an overall improvement in health along with extended life. In short-lived species there are many examples of this sort of single gene alteration that results in overall improvement, demonstrating that the processes of evolution do not optimize for life span. Should we expect to find analogous single gene alterations in humans? That question is complicated by the fact that long-lived species such as our own exhibit life spans that are much less plastic in response to metabolic and environmental factors when compared to the life spans of short-lived species. Mice can live 40% longer in response to calorie restriction, 70% longer in response to growth hormone receptor knockout, but in humans neither of those states appears to result in more than a few years gained.
Dopaminergic neurons are critical modulators for essential brain functions such as learning and memory, reward and addiction, motor control, and metabolism. My recent work identified a novel function of dopaminergic neurons in regulating aging and longevity in flies. I demonstrated that overexpressing the putative scaffolding protein Mask in small subsets of dopaminergic neurons significantly extends the lifespan in flies. Interestingly, the prolonged lifespan of the Mask-overexpressing flies is accompanied by sustained reproductive activities, contradicting the long-acknowledged inverse relation between reproduction and longevity.
This prevalent negative correlation between reproduction and longevity has been explained by the disposability theory that posits a competing allocation of energy between reproduction and somatic maintenance. However, my work, together with a few other findings in flies, suggested that extension of both lifespan and reproduction can be induced simultaneously by a variety of specific genetic manipulations. Moreover, such a co-extension also occurs in nature - the reproductive females of eusocial insects acquire physiological transformations that enable the expansion of both their reproduction capacity and lifespan.
It seems that a common mechanism may exist to actively induce adaptations to cope with the reproductive demands of the animals, which also at the same time intervenes the aging process and extends the lifespan. Inspired by this notion, I propose a reproduction-centered theory that explains the seemingly contradictory relationships of reproduction and longevity. The success of reproduction is essential for the survival of the species. From such a reproduction-centered perspective, the maintenance of the somatic tissues is not just critical for the survival of individuals but is, more importantly, essential for the fulfillment of reproduction. Therefore, I postulate that somatic tissues possess the ability to adapt to, instead of competing with, the animal's reproduction states and that such adaptations can consequentially impact aging and longevity.