Fight Aging! Newsletter, September 20th 2021

In the Alzheimer's cascade hypothesis, plaques unleash tangles; alas, where neuroinflammation fits in has been hazy. Now, the first study to combine imaging of microglial activation with amyloid and tau PET in the human brain places neuroinflammation squarely in between the two. Researchers report PET findings from 108 adults who range from cognitively healthy to Alzheimer's disease (AD) dementia. Across this cohort, the regional distribution of microglial activation mirrored Braak staging, and correlated with tangle load. Moreover, the extent of microglial activation predicted the spread of tangles into later Braak regions, suggesting it drove this pathology. Notably, the relationship between neuroinflammation and tangles only occurred in the presence of amyloid plaques, and all three pathologies were required for cognitive decline.

"Amyloid potentiates microglial activation to drive tau propagation in the brain. The data suggest neuroinflammation should be included in biological definitions of AD. This is a very compelling study, and certainly advances our understanding of the crosstalk between microglial activation, amyloid, and tau burden in the clinical context."

PET imaging studies have consistently shown that as plaques spread into cortex, tangles break out of the medial temporal lobe to rampage across the brain, attacking cognition as they go. But the mechanistic connection between the pathologies remained mysterious. The medial temporal lobe contains little amyloid, making a direct interaction unlikely. Animal and in vitro studies hinted that microglia might be the missing link. In mice, activation of the NLRP3 inflammasome in microglia caused the cells to spew cytokines that triggered tau phosphorylation in neurons. Further, microglia isolated from AD brains contained tau seeds, which the cells released into the culture medium. The data implied that microglia phagocytose aggregated neuronal tau present in aging brain, then try but fail to digest it, and instead end up strewing it across the brain.

With the goal of building better connections between pharma companies and the longevity field, ARDD's organisers are conscious of the importance of showcasing the most credible research and development in aging. "People want to believe in longevity, but it's important to maintain a stringent a scientific focus as possible. We haven't shown a single molecule working in humans and, while we've been able to slow aging down in mammals, we have never been able to stop it. But I'm very enthusiastic and positive about some of these challenges that we're facing. Years ago, the aging field was many disconnected fields. But the industry and the science has started taking shape, and the conference has evolved through the integration of multiple fields with key hallmarks of aging."

The theme of education continues throughout this year's conference, which has its roots in bridging the gap between the longevity field and major pharmaceutical companies. "From the very beginning, we have tried to make this conference very friendly towards the pharmaceutical industry, which needs to buy into this field. There has been a lot of activity in early stage drug discovery in the pharmaceutical industry, specifically on aging and age-associated biology that can be purposed towards multiple diseases."

Anne-Ulrike Trendelenburg from the Novartis Institutes for Biomedical Research gave a brilliant presentation on pathways that should be targeted to treat age-related diseases, and how her research is shifting away from aging and towards defining and targeting frailty. Novartis' research has highlighted five recommendations to guide the future of age-related disease targeting. Firstly, focusing on healthspan as opposed to lifespan, which will have the biggest impact on patient lives, adding quality of life to years, over adding years to life. Trendelenburg also highlighted targeting multimorbidity, rather than continuing to focus on treating each individual disease, which is said to be ineffective and expensive. The team from Novartis want to develop better multimorbidity models in order to progress another of their recommendations, which is to target frailty over age through clinical trials.

The day showcased a variety of longevity research, we heard more about the importance of focussing on mitochondrial targets in relation to finding age-related therapies. Karl Lenhard Rudolph from the Leibniz Institute on Aging spoke on mitochondrial enhancement and its relationship with late life dietary restriction, enabling improvements in stem cells and lifespan. While recognising the positive effects seen with dietary restriction across organisms, Rudolph addressed the worrying data that saw this method losing efficacy when restriction is started late in life. When looking at reduction of mortality rates lifelong dietary restriction shows a reduction in mortality rate, however late life dietary restriction has very little effect.

Lower-quality, clickbait-hungry media outlets love sensationalist claims, but one does expect better from the public relations department of an internationally-respected research university. And it was an easy jump from the already-overstated "In First, Aging Stopped in Humans" and "treatments can reverse two processes associated with aging and its illnesses" to saying that a treatment "can reverse aging process" - and to then land in a mud-pit of self-parody with "Human ageing reversed in 'Holy Grail' study, scientists say."

The actual findings of a recent study on hyperbaric oxygen treatment (HBOT) were much more limited. Despite some intriguing indicators, the actual impact of HBOT on aging based on this study is entirely unclear, quite plausibly negligible, and in any case objectively less impressive than that of (say) regular exercise, which certainly does not "reverse aging."

The actual details of the study show that even the narrow claims of the study abstract aren't fully justified. It's not clear that blood-cell telomeres were lengthened any more than they would have been without HBOT; it's not clear that "senescent" T-cells were reduced in numbers, let alone actually destroyed; and if "senescent" T-cells had been destroyed, it would not demonstrate a senolytic effect of HBOT. Despite the fact that it's standard terminology in the immunology world, "senescent" T-cells aren't actually "senescent cells" in the sense usually used in the geroscience world. Jumping from post-HBOT reductions in the number of these "senescent" T-cells to potential effects on classical senescent cells is really just a misunderstanding of what kinds of cells are involved in each case.

Even if the study had robustly demonstrated that every one of the points above really did occur, it would not constitute "reversing aging" - or even justify the more restrained claims that "blood cells actually grow younger as the treatments progress" or "that the aging process can in fact be reversed at the basic cellular-molecular level."

Cellular garbage disposal is critical for recycling defective cell constituents, such as proteins and organelles, towards the maintenance of cellular homeostasis. One of the main degradative molecule pathways is autophagy, which is a physiological catabolic process shared by all eukaryotes. Derived from the Greek words 'auto' meaning self, and 'phagy', meaning eating, autophagy, it was initially considered to be a bulk degradation process, while now its highly selective nature is increasingly appreciated. This self-digestive mechanism relieves the cell from proteotoxic, genotoxic, oxidative, and nutrient stress. It is accomplished in an intricate stepwise manner, which leads to clearance of damaged cell constituents, in the degradative organelle, the lysosome. Failure to complete this procedure has been implicated in many age-related diseases.

Homeostatic mechanisms that respond to mitochondrial damage are less efficient during aging. Mitophagy is a physiological eukaryotic pathway, which involves the degradation of superfluous or damaged mitochondria. When perturbed, normal mitochondrial function is hindered, resulting in the production of excessive reactive oxygen species (ROS). This ultimately leads to cellular dysfunction and tissue damage. Defective mitophagy is evident in a variety of age-related pathologies such as neurodegeneration, metabolic syndromes, and myopathies.

Aggrephagy degrades aggregation-prone proteins via targeted macroautophagy, in addition to chaperone-mediated autophagy and the proteasomal pathway. These proteins typically form aggresomes near the nucleus, which are surrounded by intermediate filament cytoskeleton, and are further processed to be degraded by autophagy. Protein aggregation usually occurs due to misfolding and can cause, among others, dysregulation of calcium homeostasis, inflammation, neurotoxicity.

Recycling of peroxisomes is also regulated by autophagy. These small dynamic single membrane organelles regulate fatty acid oxidation, production of bile acid and other lipids, while also producing ROS, which is neutralized by catalase. Moreover, peroxisomes interact with a multitude of other cellular constituents, such as lipids, the endoplasmic reticulum (ER), and mitochondria. Pexophagy and peroxisome biogenesis have recently been implicated with disease. During aging, peroxisomal targeting signal 1 (PTS1) protein import deteriorates and catalase function is diminished. Peroxisomes become more abundant and PEX5 accumulates on their membranes. This causes increased production of ROS, which further blocks peroxisomal protein import and contributes to aging.

With regard to therapeutic intervention, several pharmacological compounds have been shown to activate mitophagy and alleviate symptoms of age-related diseases, dependent on dysfunctional mitochondria. Rapamycin activates AMPK, while blocking mTOR, maintaining energetic demands and preventing neurological symptoms, such as neuroinflammation. Metformin and pifithrin induce Parkin by inhibiting p53 activity and alleviating diabetic phenotypes. Resveratrol, mainly found in grape skin, as well as, NAD+ precursors found in natural compounds activate mitophagy and mitochondrial biogenesis through the sirtuin 1 (SIRT1)-PGC-1α axis. Urolithin A, an intestinal microbiome-derived metabolite from dietary intake, induces both mitochondrial degradation and biogenesis, and increases health span of model organisms such as C. elegans and mice.

Selective autophagic induction by genetic intervention or chemical compound administration is currently being investigated in multiple diseases as potential therapeutic approach, although no drug has reached the clinic yet. Indeed, clinical studies concerning druggable autophagy targets remains limited. This highlights the complexity and intricacies of selective autophagic pathways, which in humans, cannot be easily targeted due to context-dependence and extensive crosstalk with other functional networks. Thus, initial optimism has subsided, with research now focusing on specific compounds that could target specific aspects of selective autophagy. An important objective of the collective efforts of the research community and pharmaceutical companies is to achieve targeting selective autophagy mediators, while not affecting other cellular processes.

A recent addition to the anti-ageing strategies being developed comes from cellular reprogramming approaches. Induced pluripotency studies provided evidence that age-related cellular phenotypes such as mitochondrial morphology, function and number, as well as nuclear envelope integrity, are not irreversible. However, developmental cellular reprogramming turns a cell to a pluripotent state, where it has the potential to generate any somatic cell type. This process is not appropriate for an anti-ageing therapy in vivo because it requires not only the loss of the original cellular identity, but also the re-establishment of self-renewal capabilities. Therefore, induction of pluripotency or the direct injection of pluripotent cells in vivo, invariably lead to cancer in mice. For a cellular reprogramming-based intervention to be considered rejuvenative (turning an old cell into a younger cell), we need to uncouple its effects from dedifferentiation (loss of somatic cell identity).

Cellular reprogramming has demonstrated potential not only in regenerative medicine, but also in the ageing field through the amelioration of both physiological and cellular ageing hallmarks. While partial reprogramming might be used as a catch-all term to describe this type of rejuvenation, it does not reflect the fact that the interrupted cellular reprogramming techniques that are described here are applied with the aim of (epigenetic) rejuvenation as opposed to inducing pluripotency (loss of cell identity). Reprogramming-induced rejuvenation (RIR) is a better term, capturing the nature of the utilised process and final aim of the interventions.

RIR has shown promise as a treatment to safely reverse ageing whilst retaining the ability to revert to or maintain original cell identity, both in vivo and in vitro. However, the precise nature of RIR still needs to be fully understood before it can be safely implemented as an anti-ageing treatment. For example, tracking any traces of pluripotency in partially reprogrammed cells (particularly in vivo) is a necessary precaution to minimise long-term cancer risk. Additionally, can rejuvenated partially reprogrammed cells be cultured long-term? The rejuvenated phenotype of some OSKM-treated cells lasts at least four weeks, but does this phenotype remain stable or eventually start to deteriorate at a rate faster than normal ageing?

Other important RIR safety concerns include how the reprogramming factors are introduced in vivo. Retroviruses are commonly used to integrate reprogramming factors into the genome. However, this method bears risks, such as insertional mutagenesis, residual expression and re-activation of reprogramming factors, and retrotransposon activation, all of which could increase cancer risk in vivo. Non-integrative delivery methods, such as transient transfection, non-integrating viral vectors, and RNA transfection are safer alternatives. For example, researchers have successfully used mRNA transfection to non-integratively conduct RIR. Another safe alternative is chemical-based reprogramming, which involves direct conversion of a somatic cell to a pluripotent state by use of small molecules and growth factors. It is conceivable that, in the future, chemical-based reprogramming could be adapted to achieve rejuvenation, however, this reprogramming approach currently only works for mice.

While RIR applied to skeletal muscle stem cells appears effective in improving regenerative capacity and muscle function in immunocompromised mice, further analysis is required regarding the somatic mosaicism of partially reprogrammed stem cells. Somatic variants at a stem or early progenitor cell level in turn can cause lineage bias, reduced stem cell function, and increased risk of developing haematologic cancer (e.g. age-related clonal haematopoesis). This can lead to the development of pre-malignant cells, which have a higher propensity to transform to a malignant state, the effect of which could be attenuated or exacerbated by RIR.

It also remains to be further explored whether and how RIR would work on post-mitotic terminally differentiated cells, such as neurons, cardiomyocytes, or adipocytes, but also other non-dividing cells such as quiescent or senescent cells. Pilot work has been done in the latter two states, demonstrating that a rejuvenated phenotype is achievable after restoration of cell division. These results may point to a scenario where proliferation is an essential requirement for rejuvenation. Indeed, induced pluripotency of postnatal neurons was only possible after forced cell proliferation via p53 expression. Coincidentally, the natural rejuvenation event in the early mouse embryo spans over stages of very active cell proliferation.

Overall, RIR is currently the best prospect to achieve epigenetic rejuvenation. Further studies are required to fully determine its limitations and efficacy.

Children with Hutchinson-Gilford progeria syndrome (HGPS) age rapidly due to a rare de novo mutation which causes accumulation of a shortened form of prelamin A - called progerin - at the nuclear envelope. Progerin is toxic and causes misshapen nuclei, cell senescence, a host of aging-related disease phenotypes, and death in the teenage years from myocardial infarction or stroke. Because progerin is methylated by the enzyme ICMT, earlier studies hypothesized that targeting ICMT might be an effective anti-HGPS therapy. These studies showed that targeting ICMT with genetic strategies improves phenotypes and extends survival in mouse models of progeria and that early-stage ICMT inhibitors can overcome senescence and improve phenotypes of cells from HGPS patients.

However, further studies were not possible due to the lack of ICMT inhibitors with ample bioavailability and pharmacological properties. Scientists have now taken a big step forward by synthesizing and validating a potent ICMT inhibitor (UCM-13207, Cpd21) that can be used in vivo. Their drug improves both cellular and in vivo phenotypes of HGPS, including parts of the vascular phenotype, and extends survival of mice with progeria. The study represents an important step in the preclinical validation of this therapeutic strategy and raises hopes that clinical trials might be possible in the not-too-distant future.

Both the current and previous studies show that targeting ICMT mislocalizes progerin, alleviates senescence, and stimulates proliferation of cells from mice and children with HGPS. Both also show that targeting ICMT does not influence the characteristic nuclear blebbing phenotype of progerin-expressing cells. Moreover, the magnitude of the effects of these three approaches is comparable. Whereas the earlier studies find that blocking progerin methylation reduces its turnover and causes the protein to accumulate in the nucleoplasm, Cpd21 was found to increase progerin turnover and reduce its levels in cells and tissues. The latter result - reducing the levels of a toxic protein - is obviously more attractive from a therapeutic perspective, and it raises the questions of whether Cpd21 causes off-target effects that trigger progerin degradation or whether it influences LMNA transcription, splicing, or mRNA turnover. The current study did not distinguish between these possibilities.

A number of anti-cancer strategies, which are based on chemotherapy, radiotherapy, and immunotherapy or the use of CDK4/CDK6 inhibitors and epigenetic modulators may promote cellular senescence in cancer and normal cells and tissues as an adverse side effect. Cellular senescence, a state of permanent cell cycle arrest with well characterized biochemical and molecular biomarkers, is considered to be a tumor suppressor mechanism and tissue repair and regeneration modulator. However, in some circumstances, cellular senescence may also stimulate chronic inflammation and tumorigenesis in aged organisms.

DNMT2/TRDMT1 methyltransferase is implicated in the regulation of cellular lifespan and DNA damage response (DDR). It was suggested that DNMT2/TRDMT1 might be considered as a novel target in cancer therapy as the loss of DNMT2/TRDMT1 sensitized cancer cells to PARP inhibitors. In the present study, the responses to senescence-inducing concentrations of doxorubicin and etoposide in different cancer cells with DNMT2/TRDMT1 gene knockout were evaluated, including changes in the cell cycle, apoptosis, autophagy, interleukin levels, genetic stability and DDR.

Diverse responses were revealed that was based on type of cancer cells (breast and cervical cancer, osteosarcoma and glioblastoma cells) and anti-cancer drugs. DNMT2/TRDMT1 gene knockout in drug-treated glioblastoma cells resulted in decreased number of apoptotic and senescent cells, IL-8 levels, and autophagy, and increased number of necrotic cells, DNA damage, and affected DDR compared to drug-treated glioblastoma cells with unmodified levels of DNMT2/TRDMT1. We suggest that DNMT2/TRDMT1 gene knockout in selected experimental settings may potentiate some adverse effects associated with chemotherapy-induced senescence.

Almost every cell, including stem cells, naturally release extracellular vesicles (EVs) responsible for cell-to-cell communication. They are split into three categories: microvesicles or ectosomes are submicron vesicles with a diameter of 100nm-1000nm, distinguished by biogenesis mechanisms, including cytoskeleton remodeling and phosphatidylserine externalization. These microvesicles are formed by the outward budding and fission of the plasma membrane after cell stimulation or stress. Exosomes are the most common EVs studied and the smallest ones with a diameter of 30nm-100nm.

Exosomes are considered key regulators of many biological settings and are present in several extracellular fluids to mediate cellular communication. Recently, they were suggested as biomarkers for several diseases to set up diagnosis and disease progression. Their characteristics hold a great interest in designing therapeutic purposes in metabolic and genetic disorders, neurodegenerative and cardiovascular diseases, and cancer.

The first signature of human aging is the decrease of tissue regeneration and repair, leading to the accumulation of senescent cells. These cells have been described to release more exosomes with different compositions than a normal cell. A cellular transcriptional program is induced whereby the number and composition of exosomes are changed, consequently reflecting the current parent cell profile. Much evidence has increasingly involved exosomes and exosome-derived miRNAs in both normal and pathological aging processes. Evidence has also increasingly involved exosome-derived miRNAs in aging-associated diseases. In this work, we review exosome biogenesis and its involvement in the mechanisms related to aging with a focus on the different pathways described for their secreted miRNAs.

Studies of human tissues and mouse models have shown an increased incidence of senescent cells during intervertebral disc aging and degeneration. Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice.

We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types.

Our results show that the D + Q combination could target senescence in the mouse disc, and these results provide proof of principle that senolytics may be useful in mitigating age-dependent disc degeneration by decreasing local senescence status, fibrosis and matrix degradation, while promoting cell viability, healthy matrix deposition and lower levels of systemic inflammation.

In a first for the field, there is now a hint that a tau immunotherapy may have slightly benefited people with Alzheimer's disease (AD). Semorinemab, a monoclonal antibody specific for tau's N-terminus, stemmed cognitive decline by almost half among people with mild to moderate AD, according to topline results from the Phase 2 LAURIET trial. The findings are a welcome reprieve after most tau immunotherapies thus far, including semorinemab itself, have come up short in trials. In a previous Phase 2 study, called TAURIEL, semorinemab brought no cognitive or functional benefit to people with prodromal AD or mild cognitive impairment. Despite this negative result among people in earlier stages of the disease, the companies moved forward with LAURIET, which enrolled participants in the mild to moderate stages of AD.

LAURIET enrolled 272 participants whose Mini-Mental State Examination (MMSE) scores were between 16 and 21 and who had brain amyloid at baseline. After receiving three doses spaced two weeks apart, participants received monthly intravenous infusions of semorinemab, or placebo, for the remainder of the trial. The study enrolled two cohorts, which received treatment for either 48 or 60 weeks. For both enrolled cohorts, between baseline and 49 weeks, those in the semorinemab groups declined 43.6 percent less on the ADAS-Cog11 than did those in the placebo groups, satisfying one primary outcome. The same was not true for the other primary endpoint, the Alzheimer's Disease Cooperative Study-Activities of Daily Living. Both groups declined similarly on the ADCS-ADL, in which an appointed caregiver scores the participant on how they perform a variety of tasks.

Why a possible efficacy signal in LAURIET, but not a peep in TAURIEL? Researchers think that the difference could come down to which species of tau predominate in different stages of the disease. Perhaps specific hyperphosphorylated forms drive the earlier stages of disease, and semorinemab might not bind them.

Researchers have made a surprising discovery about the connection between protein shape and mitochondrial health, providing a piece of evidence for yet another theme in aging research: it's always more complicated than we thought. Proteins within the mitochondria are intricately involved in mitochondrial function, and are protected by the mitochondrial unfolded protein response (UPRmt). When proteins misfold in the mitochondria, which can be caused by external threats like pathogens or mitochondrial toxins, the UPRmt gets activated which helps restore protein shape and function. Past research on the microscopic worm C. elegans has demonstrated that boosting the UPRmt during development contributes to better mitochondrial health and a longer lifespan for the worms.

Consistently, pharmacologically boosting UPRmt has been shown to slow down diseases with mitochondrial dysfunction, such as Alzheimer's. The new research has found that activating the UPRmt in adult worms has the opposite effect: adult worms with a boosted unfolded protein response have worse health and a shorter lifespan. Digging into the details of this surprising outcome led the team to examine the mitochondrial permeability transition pore. Most of the time this pore is closed, keeping the interior of the mitochondria separate from the rest of the cell. Under stress, though, it opens to release calcium into the rest of the cell, signaling that it's time to cut its losses and induce cell death. It turns out that methods to boost the UPRmt in adult C. elegans are caused indirectly - the UPRmt is initiated in response to the opening of the transition pore. While the UPRmt is busy trying to clean things up, the signals coming from the opened pore are too strong for the cell to ignore and result in cell death. Researchers think this is what contributes to the early death of the adult worms.

Research in C. elegans forms the basis of much aging research, but what does this mean for efforts to boost health and prevent disease in people? While the mitochondrial permeability transition pore is already implicated in conditions like stroke and heart attack, the role of the UPRmt is not as well understood. Researchers liken the UPRmt to inflammation, which has a specific purpose and is useful under some conditions, but causes damage under others. One possibility is that, in a stressed cell, the UPRmt uses valuable cellular resources, hastening the already inevitable cell death.

Multiple studies suggest that the presence of lysosomal cholesterol accumulation in macrophages, and not the total amount of intracellular lipids, is critical for the observed inflammatory response. We have shown that lysosomes in macrophages are a site of low-density lipoprotein (LDL) oxidation. Seven days after taking up mechanically aggregated LDL or sphingomyelinase aggregated LDL, mouse or human macrophage-like cells and human monocyte-derived macrophages generated ceroid in their lysosomes. Ceroid (lipofuscin) is a polymerized product of lipid oxidation found within foam cells in atherosclerotic lesions.

The lysosomal oxidation of LDL is catalyzed by oxidation-reduction active iron present in the lysosomes of macrophages through the generation of hydroperoxyl radicals at the lysosomal pH of 4.5. This oxidation is inhibited by cysteamine (2-aminoethanethiol), an antioxidant that accumulates in lysosomes. Cysteamine is used in patients for the lysosomal storage disease cystinosis, caused by the absence of the lysosomal cystine transporter cystinosin. Recently, we have shown that cysteamine reduces atherogenic conditions caused by lysosomal LDL oxidation, such as lysosomal dysfunction, cellular senescence, and secretion of various proinflammatory cytokines, such as interleukin-1β, TNF-α, and interleukin-6, and chemokines, such as CCL2, in human macrophages.

LDL receptor-deficient mice were fed a high-fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle were analyzed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32% and 56% compared with the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesion stability, decreased ceroid, and greatly decreased oxidized phospholipids in the lesions. The liver lipid levels and expression of cluster of differentiation 68, acetyl-coenzyme A acetyltransferase 2, cytochromes P450 (CYP)27, and proinflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triacylglycerol concentrations attributable to cysteamine.

In conclusion, inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.

Cellular rejuvenation occurs naturally in embryonic development when sperm and egg (each having a certain chronological age) fuse to each other to form an embryo of age zero. Similarly, reprogramming of somatic cells to pluripotency, producing induced pluripotent stem cells (iPSCs), resets their biological clock as well. At this stage, a core network of transcription factors including NANOG, OCT4, and SOX2 maintains pluripotency in embryonic stem cells (ESCs) and iPSCs. In particular, the pluripotency factor NANOG is essential for maintaining the self-renewal of ESCs over many population doublings.

Although overexpression of NANOG does not confer pluripotency to somatic cells, it has been shown to restore several cellular functions that are compromised by aging including proliferation and differentiation of senescent fibroblasts and mesenchymal stem cells. In vivo endogenous expression of this transcription factor in stratified epithelia of adult mice showed that systemic overexpression of NANOG induces hyperplasia without initiating tumors.

Recently, we discovered that expression of NANOG in myoblasts restored their myogenic differentiation potential, as evidenced by expression of myogenic regulatory factors and the ability to form myotubes, which was impaired by replicative senescence. This result prompted us to investigate the anti-aging effects of NANOG on primary human myoblasts and in skeletal muscle tissue in vivo. Here, we show that overexpression of NANOG reversed the hallmarks of cellular senescence in muscle progenitors in vitro and restored the satellite cell abundance in the skeletal muscle of progeroid mice.

Although calorie restriction has been reported to extend lifespan in several organisms, animals subjected to calorie restriction consume not only fewer calories but also smaller quantities of food. Whether it is the overall restriction of calories or the coincidental reduction in the quantity of food consumed that mediates the anti-aging effects is unclear. Here, we subjected mice to five dietary interventions. We showed that both calorie and quantity restriction could improve early survival, but no maximum lifespan extension was observed in the mice fed isocaloric diet in which food quantity was reduced.

Mice fed isoquant diet with fewer calories showed maximum lifespan extension and improved health among all the groups, suggesting that calorie intake rather than food quantity consumed is the key factor for the anti-aging effect of calorie restriction. Midlife liver gene expression correlations with lifespan revealed that calorie restriction raised fatty acid biosynthesis and metabolism and biosynthesis of amino acids but inhibited carbon metabolism, indicating different effects on fatty acid metabolism and carbohydrate metabolism. Our data illustrate the effects of calories and food quantity on the lifespan extension by calorie restriction and their potential mechanisms, which will provide guidance on the application of calorie restriction to humans.

Various mechanisms can cause sensorineural hearing loss, among which irreversible damage to inner ear hair cells is the main cause. Although the commonly used hearing aids and cochlear implants in clinical practice improve the hearing of patients, their effect depends on the quantity and quality of residual hair cells and spiral neurons. Therefore, the ideal way to treat sensorineural hearing loss is to regenerate hair cells, through the use of stem cells to repair the structure and function of the cochlea, so as to fundamentally restore hearing.

Stem cell therapy in the auditory field has been a research hotspot in recent years. Although some progress has been made, almost all are results at the animal level, and there is still a long way to go before clinical transformation. The microenvironment of inner ear stem cells and the interaction with neighboring cells are very important for inner ear stem cells or sensory precursor cells to induce differentiation into mature inner ear hair cells. In the reported studies, the efficiency of differentiation of inner ear stem cells or sensory precursor cells into hair cells is still low. An insufficient number of new hair cells, immature new hair cells without the function of mature hair cells, and long-term survival of new hair cells are all key problems and difficulties that need to be solved urgently.

These results indicate that it is more difficult to regulate a single signal pathway to regenerate functional hair cells, and it may require coordinated regulation of multiple genes to effectively promote hair cell regeneration and the functional maturity and survival of new hair cells. Still, inducing the committed differentiation of stem cells into hair cells or nerve cells, the exploration of the methods of stem cell transplantation into the inner ear, and the safety research of stem cell transplantation have collectively laid the foundation for the transplantation of stem cells in vivo.