Fight Aging! Newsletter, December 26th 2022

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:

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:


  • Details on the LEV Foundation's First Study of Combined Interventions in Mice
  • Evidence for Viral Infection and Inflammation in Familial Alzheimer's Brains
  • In Search of Early Biomarkers of LATE, a Form of Dementia Related to TDP-43 Aggregation
  • A Cautious Industry View of the Promise of Senolytics
  • Longer RNA Transcripts Exhibit Greater Alterations in Amount with Aging
  • Catalase Deficiency Accelerates Aging
  • Considering Age-Related Frailty
  • Somatic Mosaicism in the Aging Brain
  • Forms of Lowered Calorie Intake Treat Even Late Stage Type 2 Diabetes
  • Enhancer DNA Sequence from Zebrafish Can Induce Targeted Heart Regeneration in Mice
  • Inflammatory T Cells Found in Cerebrospinal Fluid of Cognitive Impairment Patients
  • Correlations Between Gut Microbiome Composition and Longevity
  • A Study in Which Exercise Fails to Improve Cognitive Function
  • A Role for Raised Ceramide Levels in Sarcopenia
  • On the Aging of the Kidneys

Details on the LEV Foundation's First Study of Combined Interventions in Mice

The recently launched Longevity Escape Velocity (LEV) Foundation will, initially at least, focus on testing combinations of interventions. This work is informed by the SENS view of aging, in that degenerative aging is produced by a limited number of forms of cell and tissue damage that result from the normal operation of metabolism. These include the accumulation of senescent cells, cross-linking of the extracellular matrix, mitochondrial DNA damage, and so forth. Each form of damage produces its own contribution to a complex web of interacting downstream consequences, so while repairing any one form of damage should be beneficial, repairing more than one should be better.

Unfortunately the research and development communities operate under incentives that strongly discourage earnest work on combinations of therapies, these incentives largely resulting from the way in which intellectual property and regulation of medical development interact. Research into combined therapies is necessary to achieve the end goal of a comprehensive toolkit of rejuvenation therapies, but it is near entirely ignored as an aspect of this area of medical research. Thus philanthropic efforts are required to fill in the gap and light the way. Combined interventions are on the roadmap of the rejuvenome project, for example. And now they are a focus at the LEV Foundation.

Robust Mouse Rejuvenation - Study 1

LEV Foundation's flagship research program is a sequence of large mouse lifespan studies, each involving the administration of (various subsets of) at least four interventions that have, individually, shown promise in others' hands in extending mean and maximum mouse lifespan and healthspan. We focus on interventions that have shown efficacy when begun only after the mice have reached half their typical life expectancy, and mostly on those that specifically repair some category of accumulating, eventually pathogenic, molecular or cellular damage. The first study in this program is starting in January 2023.

Our ultimate goal in this program is to achieve "Robust Mouse Rejuvenation". We define this as an intervention, almost certainly multi-component, that: (a) is applied to mice of a strain with a historic mean lifespan of at least 30 months; (b) is initiated at an age of at least 18 months; (c) increases both mean and maximum lifespan by at least 12 months.

In each study in this program, we will examine the synergy of (typically at least four) interventions already known individually to extend mouse lifespan when started in mid-life. We will determine not only the ultimate readout of lifespan, but also the interactions between the various interventions, as revealed by the differences between the treatment groups (receiving different subsets of the interventions) in respect of the trajectories with age of cause of death, decline in different functions, etc. In this way we will add greatly to the understanding of which benefits these interventions confer and how they synergize, or possibly antagonize.

There are two key motivations for this program. One is purely biomedical: as with all mouse work with a biomedical end goal, we hope to generate data that will inform the development of therapies to let humans live longer in good health. The other could be called rhetorical, societal, political - it is to demonstrate a definitive proof of concept that aging is much more malleable than society currently insists on thinking it is, and thus must be viewed as a tractable medical problem, rather than a fact of life.

Interventions are chosen on the basis that they 1) act systemically and 2) have individually shown some lifespan-extending effect in naturally aged mice. In this way, we are specifically selecting rejuvenation therapeutics, as opposed to those which are purely preventative and/or require early life intervention. Therapies are also selected to have minimal mechanistic overlap, based on our current understanding of their mechanisms of action. The first four interventions selected for the initial study are rapamycin, hematopoietic stem cell transplant, telomerase upregulation via TERT gene therapy, and senolytic treatment.

Evidence for Viral Infection and Inflammation in Familial Alzheimer's Brains

Familial Alzheimer's disease has an earlier onset in comparison to the sporadic Alzheimer's present in much of the population, and is connected to specific variants in genes associated with amyloid-β metabolism. In some cases that means one has to be careful of drawing conclusions based on studies of familial Alzheimer's. Today's research materials note the discovery of viral infection and signs of inflammatory dysfunction in the brains of familial Alzheimer's patients. These patients are likely more vulnerable to the consequences of viral infection, such as increased generation of amyloid-β in its antimicrobial peptide role, but there is little reason to believe that they are more vulnerable to suffering persistent infections than the rest of the population.

There is an ongoing debate in the research community regarding whether or not Alzheimer's is driven in large part by persistent viral infection, such as by herpesviruses. The mechanisms look plausible, and a major role for infection status might go some way towards explaining why only some people go onto develop Alzheimer's disease. The epidemiological data for the role of viral infection is conflicted, but recent studies suggest that combinations of viruses might be required to cause issues, rather than just one infectious agent. Antiviral treatment has been shown in some studies to reduce Alzheimer's risk.

Olfactory Viral Inflammation Associated with Accelerated Onset of Alzheimer's disease

Researchers focused on the olfactory tract, olfactory bulb, and the hippocampus, the area of the brain which manages memory and learning. They examined messenger RNA in the brain tissue of six individuals who had Familial Alzheimer's disease (FAD) and tissue from a control group without AD. They found signatures of viral infection in the olfactory bulbs of the FAD group and inflammation in the olfactory tract which carries information to the hippocampus. They also discovered altered myelination in the olfactory tract. Myelin is a protective fatty layer around nerves that allows electrical impulses to move quickly and smoothly. If it's damaged, signaling stalls.

"These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to the acceleration of FAD progression. The whole olfactory pathway goes to the hippocampus. If you decrease the signaling along that pathway then you get less signaling to the hippocampus. If you don't use it, you lose it. Our hypothesis is that some viruses accelerate Alzheimer's disease."

Signatures for Viral Infection and Inflammation in the Proximal Olfactory System in Familial Alzheimer's Disease

Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation.

Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.

In Search of Early Biomarkers of LATE, a Form of Dementia Related to TDP-43 Aggregation

LATE is a comparatively recently discovered form of dementia, connected to aggregation of misfolded TDP-43, one of the few proteins in the body capable of taking on an altered form that encourages other molecules of the same protein to also adopt that form and join together to form clumps. Aggregates are disruptive of cell function, but it is a slow process to understand exactly why this is the case. Researchers have been working on understanding amyloid-β aggregates for decades now, and continue to find that the present state of knowledge is incomplete regarding how the toxic halo of biochemistry that surrounds aggregates causes dysfunction and cell death.

With the growing interest in TDP-43 pathology, researchers have in recent years found it present in many older people to a measurable degree, as is the case for other protein aggregates. It is important to work towards therapies that can clear all of these aggregates, such as potentially those based on the use of catabodies. Even in the absence of very obvious pathology, it is likely the case that protein aggregates contribute to brain aging in more subtle, indirect ways. Medin aggregates, for example, have only recently been found to likely cause pathology, and they have been known for decades.

Looking for an Early Sign of LATE

Limbic predominate age-related TDP-43 encephalopathy or LATE is a recently recognized form of dementia that affects memory, thinking, and social skills. It mimics Alzheimer's disease or AD (and sometimes co-exists with it), but LATE is a different condition, with its own risks and causes. A new study analyzed levels of TDP-43 extracted from the exosomes secreted into the blood stream by various cell types, including neurons and glial cells. Exosomes are extracellular vesicles or sacs that transport DNA, RNA, and proteins inside the cell until their release. Researchers analyzed the brains of 64 patients post-mortem, 22 with autopsy-confirmed LATE and 42 patients who died without an indication of LATE.

The researchers reported significantly elevated plasma levels of TDP-43 in confirmed LATE patients. The effect was detected only in astrocyte-derived exosomes, not neuronal or microglial exosomes. Astrocytes are a sub-type of glial cell that perform many essential functions in the central nervous system, from regulating blood flow to providing the building blocks of neurotransmitters. They outnumber neurons more than fivefold. Effective treatment of all neurological diseases depends greatly upon early diagnosis. At the moment, however, LATE can only be diagnosed after death, and it is often confounded by the fact that living patients may have both LATE and AD. The findings that increased plasma concentrations of TDP-43 could be a tell-tale indicator of LATE are encouraging.

Evaluation of blood-based, extracellular vesicles as biomarkers for aging-related TDP-43 pathology

Limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. TDP-43 was evaluated in neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs). EV preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses of disease.

TDP-43 was significantly elevated in plasma ADEVs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in EV-depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. Blood-based EVs, specifically measuring TDP-43 accumulation in ADEVs, may serve as a potential diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.

A Cautious Industry View of the Promise of Senolytics

This article on senolytic therapies to selectively remove senescent cells in old tissues is in part a matter of Unity Biotechnology talking up their position. The company suffered from first mover disadvantage in bringing senolytic drugs into clinical development. The field has made progress very rapidly over the last decade, and startups founded even just a couple of years after Unity's launch benefited from greater knowledge and a selection of better technologies to work with. Still, one can be talking up one's position and also be right. The accumulation of senescent cells is profoundly harmful, a significant contribution to degenerative aging, and senolytics are indeed a promising approach to the treatment of aging. Widespread use will greatly transform the field of medicine.

The interesting thing about small molecule senolytic therapies is that the first of these tested in animals and humans, the dasatinib and quercetin combination, is actually relative good, even though it clears at most half of the senescent cells in a given tissue, and much less than that in many tissue types. Alternative approaches that followed have struggled to improve on its effectiveness, at least going by published data. While the industry moves slowly, and approvals of new drugs are years away yet, there is little to stop an older individual deciding that the clinical trial safety profile for dasatinib and quercetin looks decent, and setting forth to try it for themselves.

Senolytic Therapies Pose Revolutionary Potential to Roll Back Diseases of Aging

Senolytic therapies are, at this point, as revolutionary as checkpoint inhibitors but with broader effectiveness. This approach delays the onset of diseases of aging by removing senescent cells from the body, thus enabling people to remain healthier longer or to regain some degree of function lost to disease. Senolytics is a new field and most of the research is still in academic centers - most notably, the Mayo Clinic. Approval of any therapeutics is years - perhaps even a decade - away. Currently, there are many unknowns. "We're at the stage where we don't know - in humans - which cells senesce and when, so there would be concern if, for example, post-mitotic cells that can't be replaced were suddenly eliminated by senolytics. We also don't know which senescent cells are the most disadvantageous."

"We're all carrying some burden of senescent cells ... usually at a benign level, and it's very likely contributing to the aging process. But, in certain stressed environments, the risk burden increases." A normal aging eye, for example, shows some accumulation of senescent cells but, when a disease - macular degeneration or diabetes, for example - is also involved, senescent cells are even more abundant. Senescent cells express the protein p16. Unity's approach identifies these cells based on their state - specifically their expression of p16 and their secretion of inflammatory factors. The company's lead asset, UBX1325, targets BCL-xl, which senescent cells - but not healthy cells - require for survival. "If you starve them of that, they are eliminated."

UBX1325 is being developed to treat diabetic macular edema (DME) and age-related macular degeneration. Upwards of 100 patients have been treated in early trials. UBX1325 is injected into the eye. As a result, the pathology of the disease is reduced, the anatomy looks good and the patients see better. The average gain was 7.5 letters or two lines on a vision chart. That gain was also seen in patients who had plateaued on anti-VEGF therapy and were treated with senolytics. A single injection appears to confer durable benefit.

"Nephrologists have begun to realize that acute accumulation of senescent cells drives progression of disease and the pathologies associated with it and that this accumulation of inflammatory cells leads to more fibrosis and more inflammation. Senolytics is exciting because it's the first of a class of therapy that has the potential to go after aging more broadly. Senescence seems to affect everyone and all the major organ systems in the body. One of the first things shown in transgenic animals was that if you remove (these cells) there was meaningful improvement in lifespan and healthspan. If we don't recognize aging as a legitimate target for medical intervention, it will be difficult to move the needle."

Oisín's Biotechnologies furthest-advanced senolytics program addresses kidney disease. One application focuses on blocking the progression of acute kidney injury toward chronic kidney disease. The other application is for people with advanced kidney disease who may be approaching renal failure. Eliminating the senescent cells probably won't return those kidneys to full function, but it may retard or halt disease progression. The goal is to eliminate the p16 cells. The company does that by targeting p16+cells with a caspase-9 suicide gene. The senescent cells then die by apoptosis. Although the p16 pathway is critical in identifying senescent cells, it may not be the only possible pathway. Recognizing that, the company's new frailty study targets both the p16 and p53 pathways, creating a synergistic, two-pronged method of killing senescent cells. That approach may be applied to its kidney program in the future.

Senolytics is a completely new type of therapy that, at this admittedly early stage, appears to have great promise. If it delivers on that promise, it will change what it means to age irrevocably.

Longer RNA Transcripts Exhibit Greater Alterations in Amount with Aging

In the process of producing proteins from genetic blueprints, the first step is transcription, the generation of RNA molecules, generally called transcripts. In today's open access paper, researchers present data to support an interesting observation: that age-related changes in the abundance of specific RNA transcripts correlate with transcript length. They offer some suggestions as to mechanisms that might contribute to this effect, such as stochastic DNA damage or dysregulated RNA splicing. RNA splicing is the part of transcription in which RNA to match specific intron and exon sections of a gene are joined together to form the transcript. In recent years researchers have noted that dysfunction arises in the splicing process with age, and that this might cause further downstream issues.

Finding a way to link stochastic DNA damage to the common manifestations of aging has been a challenge. In and of itself, near all stochastic DNA damage doesn't do much obvious harm to any given cell: most of the altered genes are not used in that cell, and, with the exception of the risk of cancer, most of the mutational alterations to DNA are not that important. Further, this sort of damage is completely different in every cell it happens in. So how does it give rise the fairly uniform set of changes noted in aging? Possibilities include (a) somatic mosaicism, in which only the few problematic changes occurring in stem cells matter, as they spread throughout tissues, and (b) the recently discovered way in which double strand break repair may cause the epigenetic alterations that are characteristic of aging, by exhausting resources needed for the correct maintenance of chromatin.

In the context of today's data, it is interesting to consider ways in which stochastic DNA damage might cause uniform disarray in RNA splicing. This might perhaps occur through a similar mechanism to the above mentioned double strand break repair mechanism, some form of resulting alteration in epigenetic patterns as a response to damage that leads to changed expression of critical splicing factors, for example.

Aging is associated with a systemic length-associated transcriptome imbalance

Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan.

Perhaps the most pressing question relates to the origin of the length-associated transcriptome imbalance during aging. Our findings about the genes with the shortest and longest transcripts enriching for genes with different roles toward longevity could be viewed as support for longevity-related roles of genes driving the evolution of their transcript length. However, this explanation would presently only appear to account for a fraction of the genes that show a transcript length-associated change during aging.

Turning to earlier literature, a length-associated transcriptome imbalance does not appear specific to aging itself. Moreover, there seem to be multiple potential molecular origins for a length-associated transcriptome imbalance. Most prominent among the specific molecular mechanisms, DNA damage has been explicitly demonstrated to yield a length-associated transcriptome imbalance with a relative fold decrease of the longest transcripts in a progeroid model of aging. Heat shock, which challenges proteostasis, a hallmark of aging, leads to a length-associated transcriptome imbalance by causing premature transcriptional termination through cryptic intronic polyadenylation. Similarly, loss of splicing factor proline/glutamine (Sfpq), encoded by the gene that displays the strongest differential splicing during human aging, has been shown to yield a length-associated transcriptome imbalance by interfering with transcriptional elongation of long genes. Methyl CpG binding protein 2 (MeCP2) opposes a length-associated transcriptome imbalance by dysregulating transcriptional initiation according to the length of the gene body. Further, patients with Alzheimer's disease show a length-associated transcriptome imbalance whose onset has been suspected to stem from somatic mutations that affected transcript stability.

Jointly, these observations invite the unsupported hypotheses that during aging there may not be a single origin for the length-associated transcriptome imbalance and that the length-associated transcriptome imbalance in aging instead represents an intermediate step through which multiple environmental and internal conditions simultaneously affect multiple downstream outputs. The length-associated transcriptome imbalance thus may offer itself as an explanation for the recent observation of inter-tissue convergence of gene expression during aging. Further arguing in favor of an integrative role of the length-associated transcriptome imbalance, we find evidence that several distinct antiaging interventions counter the length-associated transcriptome imbalance against long transcripts despite the point that these different antiaging interventions partially affect different aspects of cellular and organismal physiology.

Catalase Deficiency Accelerates Aging

Catalase is an important antioxidant enzyme, defending cells against oxidative stress. Aging brings with it mitochondrial dysfunction and other sources of excess oxidative molecules, and some animal studies have shown improved health to result from upregulation of catalase expression. Regardless of whether or not more of a given molecule in cells is beneficial, it is often the case that removing it is harmful, and thus it is usually hard to draw conclusions based on gene knockout studies as to whether a given molecule is a potential target for upregulation.

Lysosomes are a central hub for cellular metabolism and are involved in the regulation of cell homeostasis through the degradation or recycling of unwanted or dysfunctional organelles through the autophagy pathway. Catalase, a peroxisomal enzyme, plays an important role in cellular antioxidant defense by decomposing hydrogen peroxide into water and oxygen.Both impaired lysosomes and catalase have been linked to many age-related pathologies with a decline in lifespan.

Aging is characterized by progressive accumulation of macromolecular damage and the production of high levels of reactive oxygen species. Although lysosomes degrade the most long-lived proteins and organelles via the autophagic pathway, the role of lysosomes and their effect on catalase during aging is not known. The present study investigated the role of catalase and lysosomal function in catalase-knockout (KO) mice.

We performed experiments on wild-type (WT) and catalase KO younger (9 weeks) and mature adult (53 weeks) male mice and mouse embryonic fibroblasts isolated from WT and KO mice from E13.5 embryos as in vivo and in ex vivo respectively. We found that at the age of 53 weeks (mature adult), catalase-KO mice exhibited an aging phenotype faster than WT mice. We also found that mature adult catalase-KO mice induced leaky lysosome by progressive accumulation of lysosomal content, such as cathespin D, into the cytosol. Leaky lysosomes inhibited autophagosome formation and triggered impaired autophagy. The dysregulation of autophagy triggered mTORC1 activation. However, the antioxidant N-acetyl-L-cysteine and mTORC1 inhibitor rapamycin rescued leaky lysosomes and aging phenotypes in catalase-deficient mature adult mice.

Considering Age-Related Frailty

Frailty is an end stage of aging, characterized by physical weakness, chronic inflammation, and lack of robustness in response to challenges. Frail individuals tend to spiral downward into organ failure and death in response to adverse circumstances, such as infection or injury, that less frail, younger individuals can survive. The question of how to reverse frailty is an important one; in principle, a good enough way of addressing the underlying causative mechanisms of aging would lead to improvement in patient outcomes. A number of the groups involved in development of first generation age-slowing and rejuvenating therapies are looking to frailty as a target for initial clinical trials.

Frailty is a multi-dimensional and dynamic condition, theoretically defined as "a state of increased vulnerability, resulting from age-associated declines in reserve and function across multiple physiologic systems, such that the ability to cope with every day or acute stressors is compromised". Although declines in physiological reserve are associated with senescence in the normal ageing process, frailty is an extreme consequence of this process, where this decline is accelerated and homeostatic responses begin to fail.

Frailty is a common and clinically significant condition among older adults. This is predominantly due to its association with adverse health outcomes, such as hospitalisation, falls, disability, and mortality. All older adults are susceptible to the risk of developing frailty, and even their younger counterparts. However, this risk is significantly increased with increases in chronological age, in the presence of comorbidities, low physical activity, poor dietary intake, and low-socioeconomic status, among a number of other factors.

While frailty is a dynamic condition, with the possibility of bi-directional transition between frailty states, this transition is more commonly progressive. This is largely due to the association of frailty with a plethora of adverse health outcomes, which can often lead to a spiral of decline. As frailty progresses, interventions to mitigate, manage, or reverse this decline become increasingly difficult to implement, both from practical and physiological perspectives.

The relative prevalence of frailty in older adults may be reduced with future improvements in treatment, particularly those identified as effective at mitigating the onset of frailty. However, irrespective of this, the absolute prevalence, and overall burden of frailty is projected to increase dramatically in the coming decades as the population ages. Perhaps of most concern in this regard, is that several longitudinal birth cohort studies have reported increases in the relative prevalence of frailty among more contemporary generations of older adults, when compared to their generational predecessors.

Somatic Mosaicism in the Aging Brain

Somatic mosaicism is the result of the random mutational damage that occurs to stem cells and progenitor cells, leading to a spread of different mutation patterns throughout the descendant cells making up a tissue. It is thought to be involved in aging, a way for random mutation, different in every cell, to lead to specific dysfunctions occurring throughout a tissue, and potentially prime a tissue for a later combination of mutations that gives rise to cancer. This commentary on recent research discusses somatic mosaicism in the brain, intending to see whether there were differences in neurological disease states, but the findings are more relevant to cancer risk.

Mutagenesis occurs in human cells starting from the fertilized egg and continuing throughout life, resulting in somatic mutations. Most somatic mutations are functionally benign and have neither harmful nor beneficial effects on health. In rare cases, they change cell functions and may lead to diseases. Cancer is the most common example of a genetic disorder caused by somatic mutations.

In our recent study, we analyzed 131 post-mortem human brains from 44 healthy individuals, 19 with Tourette syndrome, nine with schizophrenia and 59 with autism spectrum disorder. The study reported several interesting findings by whole-genome sequencing of the brains to a depth of over 200X. First, most brains had 20-60 detectable single-nucleotide mutations that likely arose in early development. There were no differences in the somatic mutation burden between diseased and normal brains. Unexpectedly, seven brains, about 6% of the total, carried an abnormally large number - at least 100 but as many as 2000 - of somatic mutations. This phenomenon was termed hypermutability. Hypermutability increased with age, reaching ∼16% among old brains (older than 60 years of age), while it was only ∼2% among younger brains (less than 40 years of age). Interestingly, 10 damaging mutations in cancer-driving genes were found in four of the other six hypermutable brains, therefore implying clonal expansion. Consistently, hypermutability is typically localized to one brain region, although that estimate could be biased as no more than two regions per brain were analyzed.

Age is known to be the major factor associated with cancer occurrence. As such, the observed hypermutability carries two major hallmarks of cancers: clonal expansion and age association. This suggests that hypermutability generally represents pre-cancer or undiagnosed cancer cases, implying a theoretical possibility of cancer monitoring and early detection based on genomics. Association with aging also implies that hypermutability could be relevant in other aging-associated diseases such as Parkinson's and Alzheimer's. If proven, they theoretically could be diagnosed early before symptoms develop, using hypermutability as a genomic biomarker. However, it is currently unclear how this could be achieved, given that brain tissue is hardly accessible.

The question of which cell type expanded remains open. It could be interneurons. However, since the cell fractionation experiment may not isolate pure interneurons, clonally expanded cells could theoretically be some other cell type. Unlike post-mitotic neurons, glial cells continue to divide in adult brains. Given previous studies reporting increased glial cell fraction with age, the hypothesis of clonal gliogenesis is consistent with the observation that hypermutable brains are older. Clonal hematopoiesis with infiltration of blood into the brain could be yet another possibility. This hypothesis emerges from the observation that mutated cancer-driving genes in hypermutable brains are frequently associated with clonal hematopoiesis. In aging adults, clonal hematopoiesis increases, and the blood-brain barrier also becomes leakier. So, expanded cell lineages in the blood could be detected in the brain. Further studies are required to determine which hypothesis is correct, but it is possible that all could be correct, and there could be different causes of hypermutability in different individuals.

Forms of Lowered Calorie Intake Treat Even Late Stage Type 2 Diabetes

Type 2 diabetes is a lifestyle disease for near all patients. It results from excess visceral fat tissue, with some evidence suggesting that the specific issue is excess fat in the pancreas. Low calorie diets produce a reversal of symptoms, perhaps in large part due to loss of visceral fat. Here researchers show that intermittent fasting, another approach to reducing calorie intake, also helps to reduce the symptoms suffered by patients and the dependency on medication.

One might conclude that most type 2 diabetics are choosing to remain type 2 diabetics by refraining from lowered calorie intake and consequent weight loss. It isn't exactly easy to control one's diet, but then suffering type 2 diabetes seems quite challenging as well. Given the choice between those two options, it is strange that so few people choose to control their diet. Rationality is not a human specialty!

Intermittent fasting diets have become popular in recent years as an effective weight loss method. With intermittent fasting, you only eat during a specific window of time. Fasting for a certain number of hours each day or eating just one meal a couple of days a week can help your body burn fat. Research shows intermittent fasting can lower your risk of diabetes and heart disease.

Researchers conducted a 3-month intermittent fasting diet intervention among 36 people with diabetes and found almost 90% of participants, including those who took blood sugar-lowering agents and insulin, reduced their diabetes medication intake after intermittent fasting. 55% of these people experienced diabetes remission, discontinued their diabetes medication and maintained it for at least one year.

The study challenges the conventional view that diabetes remission can only be achieved in those with a shorter diabetes duration (0-6 years). Sixty-five percent of the study participants who achieved diabetes remission had a diabetes duration of more than 6 years (6-11 years). "Diabetes medications are costly and a barrier for many patients who are trying to effectively manage their diabetes. Our study saw medication costs decrease by 77% in people with diabetes after intermittent fasting."

Enhancer DNA Sequence from Zebrafish Can Induce Targeted Heart Regeneration in Mice

This very interesting work involves identifying enhancer DNA sequences that regulate regeneration in an exceptionally regenerative species, such as zebrafish, and introducing these sequences into mammals via gene therapy. The researchers find a sequence that can be used to regulate expression of genes that drive heart regeneration following injury, a desirable goal given that mammalian hearts regenerate poorly. Zebrafish are capable of scarless healing of heart injuries, and connecting the zebrafish enhancer to mammalian growth genes can improve regeneration, by expressing these genes at the appropriate time in the context of repair of injury.

Researchers borrowed a segment of zebrafish DNA that they call a TREE, tissue regeneration enhancer element. TREEs are a family of gene enhancers included in the genome that are responsible for sensing an injury and orchestrating the activity of repair-related genes for reconstruction in a specific place. These enhancers also can shut off gene activity as healing is completed. These regulatory elements have been found in fruit flies, worms, and mice as well as the zebrafish. "We probably have them too, but it's just easier for us to find them in zebrafish and ask if they work in mammals."

About 1,000 nucleotides long, these enhancer sequences are bristling with recognition sites for different factors and stimuli to attach and change gene activity. "We don't fully understand how they do this and what they're truly responding to. Different cell types within an animal also have different types of these enhancers. Some of them are responsive in multiple tissues - those are the ones we use here. But when we profile regenerating spinal cord or fins in fish, we get different sequences. There may be tens of thousands of these types of enhancers in the human genome."

Rsearchers wanted to know if they could selectively incorporate the enhancer elements into an adult mouse using adeno-associated virus, a familiar gene therapy tool for introducing gene sequences into cells. The virus introduced DNA containing an enhancer to all tissues, but the hope was that the TREEs would only become active in response to an injury. A series of experiments in heart attack models of mice showed that viruses containing a TREE could be infused a week before injury and then the enhancer would jump into action when it detected injury. But they found it also worked when introduced to the animal a day or two after the heart attack.

Then, to see if this system could actually repair damage, rather than just sensing damage and turning on a gene that lights up tissue, they delivered a hyperactivated form of YAP, a powerful tissue growth gene that is implicated in cancer. The key question was whether this "really potent hammer" that can make cell division run amok could be lassoed into working only in the right time and place. They used a mutated YAP controlled by a TREE to see whether they could have safe growth of muscle after a heart attack in mice. The TREE turned on a mutated YAP for a few weeks, just in the injury site, and then it naturally shut down expression. The treatment caused muscle cells to begin to divide and the mouse's heart returned to near normal function after several weeks, though not without some scarring.

Inflammatory T Cells Found in Cerebrospinal Fluid of Cognitive Impairment Patients

Inflammation in brain tissue is a feature of neurodegenerative conditions, and chronic inflammation is a feature of aging in general. This unresolved inflammatory signaling is disruptive to normal tissue structure and function. Researchers here note a consequence of inflammation in the innate immune cells of the brain, microglia. They produce a signal that draws in active, inflammatory T cells from the body in large numbers, which no doubt makes the situation worse. Normally there is little traffic between the separate immune systems of the brain and body, but the blood-brain barrier enforcing that separation becomes leaky with age, allowing inappropriate cells and molecules into brain tissue, where they can cause damage.

As people age, their cerebrospinal fluid (CSF) immune system becomes dysregulated. In people with cognitive impairment, such as those with Alzheimer's disease, the CSF immune system is drastically different from healthy individuals, a new study discovered. To analyze the CSF, researchers used single-cell RNA sequencing. They profiled 59 CSF immune systems from a spectrum of ages by taking CSF from participants' spines and isolating their immune cells. The first part of the study looked at CSF in 45 healthy individuals aged 54 to 83 years. The second part of the study compared those findings in the healthy group to CSF in 14 adults with cognitive impairment, as determined by their poor scores on memory tests.

Scientists observed genetic changes in the CSF immune cells in older healthy individuals that made the cells appear more activated and inflamed with advanced age. In the cognitively impaired group, inflamed T-cells cloned themselves and flowed into the CSF and brain. Scientists found the cells had an overabundance of a cell receptor - CXCR6 - that acts as an antenna. This receptor receives a signal - CXCL16 - from the degenerating brain's microglia cells to enter the brain. "It could be the degenerating brain activates these cells and causes them to clone themselves and flow to the brain. They do not belong there, and we are trying to understand whether they contribute to damage in the brain."

Correlations Between Gut Microbiome Composition and Longevity

A great deal of research is focused on cataloguing and correlating specific differences in the gut microbiome with aspects of aging. In years ahead, techniques will be developed to more precisely control the composition of the gut microbiome, removing issues such as too great a number of inflammatory microbes, or those producing harmful metabolites. At the moment, only more crude approaches such as fecal microbiota transplantation from a young donor are well developed. In principle it should be possible to take a probiotic approach and use oral administration to achieve a similar outcome, a rejuvenated gut microbiome, but the knowledge and logistics are still lacking when it comes to producing the desired combination of microbes at scale.

As a complex and dynamic ecosystem, the gut microbiota is associated with major conditions like obesity, type 2 diabetes, cardiovascular disease, and cancer. Associations between aging and gut microbiota have been well-studied. Several studies have suggested that aging is associated with the composition of the gut microbiome and its metabolites, primarily through nutrient signaling pathways, immune regulation mechanisms, and epigenetic mechanisms. Aging-related gut dysbiosis may lead to the occurrence or progression of other metabolic diseases, resulting in a loss of healthy longevity. In addition, aging-related diet patterns can influence gut microbiota health, and dietary interventions can improve intestinal health and immune status in older adults, thereby increasing their healthy longevity. However, the biological mechanism of gut microbiota affecting longevity-related traits, such as healthspan and longevity, remains elusive.

Our study explored the effect of gut microbiota on longevity based on the data from multiple independent large-scale genome wide association studies (GWAS) of gut microbiota and longevity. Findings from linkage disequilibrium score (LDSC) regression analysis indicate a suggestive genetic correlation between gut microbiota and longevity. Utilizing the independent GWAS data, we further tested the causal association between identified candidate gut microbiota and longevity-related traits using Mendelian Randomization (MR) analysis. Our results provided potential clues for the effect of gut microbiota on longevity.

LDSC analysis detected four candidate genetic correlations, including Veillonella (genetic correlation = 0.5578) and Roseburia (genetic correlation = 0.4491 for longevity, Collinsella (genetic correlation = 0.3144 for parental lifespan and Sporobacter (genetic correlation = 0.2092) for healthspan. Further MR analysis observed suggestive causation between Collinsella and parental longevity (father's age at death). Reverse MR analysis also detected several causal effects of longevity-related traits on gut microbiota, such as longevity and Sporobacter.

A Study in Which Exercise Fails to Improve Cognitive Function

It is interesting to see a study in which exercise failed to improve memory function in older adults, given the sizable number of studies showing that it does help. One possibility is that intensity of exercise matters. In general, however, the literature leans in the direction of exercise slowing cognitive decline. Yet no outcome in research is so guaranteed that there will be a complete absence of studies in which it fails to show up in the data; this is one of the challenges inherent in following the output of the scientific community.

A large study that focused on whether exercise and mindfulness training could boost cognitive function in older adults found no such improvement following either intervention. The researchers studied 585 adults ages 65 through 84. None had been diagnosed with dementia, but all had concerns about minor memory problems and other age-related cognitive declines.

All study participants were considered cognitively normal for their ages. The researchers tested them when they enrolled in the study, measuring memory and other aspects of thinking. They also conducted brain-imaging scans. The participants were randomly assigned to one of four groups: a group in which subjects worked with trained exercise instructors; a group supervised by trained experts in the practice of mindfulness; a group that participated in regular exercise and mindfulness training; and a group that did neither, but met for occasional sessions focused on general health education topics. The researchers conducted memory tests and follow-up brain scans after six months and again after 18 months.

At six months and again at 18 months, all of the groups looked similar. All four groups performed slightly better in testing, but the researchers believe that was due to practice effects as study subjects retook tests similar to what they had taken previously. Likewise, the brain scans revealed no differences between the groups that would suggest a brain benefit of the training.

A Role for Raised Ceramide Levels in Sarcopenia

Researchers here provide evidence for raised levels of ceramide in muscle tissue to be an important part of the metabolic dysfunction of aging. It reduces muscle stem cell activity, contributing to the age-related loss of muscle mass and strength that leads to sarcopenia and frailty. Whether working on this point of intervention, to produce improved ceramide blockers with fewer side-effects, is better or worse than other avenues is an open question. Altered metabolism is thought to be a fair way downstream from the root causes of aging, and tackling root causes should always be a better option. It is is very challenging to track backwards along the chain of cause and effect from an observation such as raised ceremide levels, however. Thus most research and development groups prefer to stop at this point and build a more limited intervention based on what is known now.

Researchers have discovered that when mice age, their muscles become packed with ceramides. Ceramides are sphingolipids, a class of fat molecules that are not used to produce energy but rather perform different tasks in the cell. The researchers found that, in aging, there is an overload of the protein SPT and others, all of which are needed to convert fatty acids and amino acids to ceramides.

Next, the scientists wanted to see whether reducing ceramide overload could prevent age-related decline in muscle function. They treated old mice with ceramide blockers, such as myriocin and the synthetic blocker Takeda-2, and used adeno-associated viruses to block ceramide synthesis specifically in muscle. The ceramide blockers prevented loss of muscle mass during aging, made the mice stronger, and allowed them to run longer distances while improving their coordination.

To study this effect more deeply, the scientists measured every known gene product in the muscle using a technique called RNA sequencing. They found that blockade of ceramide production activates muscle stem cells, making muscles build up more protein and shifting fiber type towards fast-twitch glycolytic to produce larger and stronger muscles in aged mice.

Finally, the scientists looked at whether reducing ceramides in muscle could also be beneficial in humans. They examined thousands of 70-80-year-old men and women, and discovered that 25% of them have a particular form of a gene that reduces the gene products of sphingolipid production pathways in muscle. The people who had this ceramide-reducing gene form were able to walk longer, be stronger, and were better able to stand up from a chair, indicating healthier aging, similar to mice treated with ceramide blockers.

On the Aging of the Kidneys

The longevity-associated gene klotho is known to act in kidney tissue, in ways that are protective of cell function in the aging environment of damage and inflammation. One of the conclusions that might be drawn from the extended life span produced by increased klotho expression in animal studies is that declining kidney function is an important aspect of aging. If the kidneys are not efficiently clearing waste from the bloodstream, and otherwise providing their contribution to bodily function, then all organs suffer as a result. Faster loss of kidney function means a faster decline into disease and mortality.

The renal condition is one of the crucial predictors of longevity; therefore, early diagnosis of any dysfunction plays an important role. The key role of the kidneys is to remove waste products from the blood and also regulate the levels of many essential compounds. Chronic kidney disease is one of the major causes of death worldwide, as well as a leading cause of years of life lost. Kidneys are highly susceptible to the aging process. Unfavorable conditions may lead to a significant disturbance of the body's homeostasis.

Despite the characteristic changes in the functioning and appearance of the kidneys being wholly assumed, the exact mechanisms of kidney senescence are still uncertain. It is challenging to distinguish between changes in the physiological aging of the kidneys and those in age-related kidney diseases and comorbidities. Apart from physiological changes, there are some conditions such as hypertension, diabetes, or obesity which contribute to the acceleration of the aging process. A determination of macroscopic and microscopic changes is essential for assessing the progression of aging. With age, we observe a decrease in the volume of renal parenchyma and an increase in adipose tissue in the renal sinuses. Senescence may also be manifested by the roughness of the kidney surface or simple renal cysts. The main microscopic changes are a thickening of the glomerular basement membrane, nephrosclerosis, an accumulation of extracellular matrix, and mesangial widening.

A vital factor that also should be taken into consideration in renal aging is oxidative stress mediated by SIRT1, PGC-1α, PPARα, and Klotho. Studies have shown that resveratrol or renin-angiotensin-aldosterone system blockers can be helpful to mitigate renal aging. Yet something that seems to be the most beneficial for renal function is simple habits such as appropriate diet and exercise.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.