During tissue regeneration, the recruitment of inflammatory cells is a critical early response to injury. This recruitment aids in the establishment of a favorable environment for progenitor function and tissue regeneration. Chemokines play an important role in the recruitment of inflammatory cells to sites of injury; however, persistently elevated signaling contributes to chronic inflammation associated with impaired regeneration. Among the large chemokine superfamily members, Ccl2, Ccl7, and Ccl8 bind a shared receptor, Ccr2, and have key roles in the deleterious consequences of chronic chemokine activity. As such, inhibition of Ccr2 is being pursued as a clinical therapy in disease contexts.

As a G-protein coupled transmembrane receptor, ligand-mediated activation of Ccr2 mobilizes intracellular G-proteins that help activate several pathways, including Erk and p38Mapk. Abnormal activity in these intracellular mediators has been implicated in age-related stem cell and progenitor cell dysfunction. A role for Ccr2 has also been described during skeletal muscle regeneration.

The regenerative capacity of skeletal muscle relies on a population of non-hematopoietic Pax7-expressing muscle stem cells called satellite cells (SCs). In adults, SCs reside in a primarily quiescent state. In response to a degenerative insult, SCs activate, proliferate, differentiate, and the derived progenitor cells fuse to form multinucleated muscle fibers (myofibers); thus, fulfilling skeletal muscle regeneration. Analogous to other tissues and organs, the regenerative potential of skeletal muscle declines with age. Although features of this decline include loss of SC number and function, a sub-population persists with a regenerative potential that can be stimulated.

The role of Ccr2 in non-hematopoietic cells is largely understudied, especially in the context of tissue regeneration and aging. Here, we find inflammatory-related Ccr2 expression in non-hematopoietic myogenic progenitors (MPs) during regeneration. After injury, the expression of Ccr2 in MPs corresponds to the levels of its ligands, the chemokines Ccl2, Ccl7, and Ccl8. We find stimulation of Ccr2-activity inhibits MP fusion and contribution to myofibers. High levels of Ccr2 chemokines are a feature of regenerating aged muscle. Correspondingly, deletion of Ccr2 in MPs is necessary for proper fusion into regenerating aged muscle. Finally, opportune Ccr2 inhibition after injury enhances aged regeneration and functional recovery. These results demonstrate that inflammatory-induced activation of Ccr2 signaling in myogenic cells contributes to aged muscle regenerative decline.

The cells of the liver normally replenish themselves, but need a healthy, nurturing environment to regenerate. However, in end-stage liver disease, the liver is bound up by scar tissue and too toxic for the cells to make a comeback. Nearly a decade ago, researchers noticed that if they injected healthy liver cells into the lymph nodes of a mouse, they would flourish, forming an auxiliary liver to take over the tasks of the animals' genetically induced malfunctioning liver. But mice are small. Researchers needed to show that a large animal could grow a meaningful mass of secondary liver tissue to overcome liver disease.

To mimic human liver disease in pigs, the researchers diverted the main blood supply from the liver, and at the same time, they removed a piece of healthy liver tissue and extracted the hepatocytes. Those liver cells were then injected into the abdominal lymph nodes of the same animal they came from. All six pigs showed a recovery of liver function, and close examination of their lymph nodes revealed not only thriving hepatocytes, but also a network of bile ducts and vasculature that spontaneously formed among the transplanted liver cells. The auxiliary livers grew bigger when the damaged tissue in the animals' native liver was more severe, indicating that the animals' bodies are maintaining an equilibrium of liver mass, rather than having runaway growth akin to cancer.

Orthotopic liver transplantation continues to be the only effective therapy for patients with end-stage liver disease. Unfortunately, many of these patients are not considered transplant candidates, lacking effective therapeutic options that would address both the irreversible progression of their hepatic failure and the control of their portal hypertension. In this prospective study, a swine model was exploited to induce sub-acute liver failure. Autologous hepatocytes, isolated from the left hepatic lobe, were transplanted into the mesenteric lymph nodes by direct cell injection.

30 to 60 days after transplantation, hepatocyte engraftment in lymph nodes was successfully identified in all transplanted animals with the degree of ectopic liver mass detected being proportional to the induced native liver injury. These ectopic livers developed within the lymph nodes showed remarkable histologic features of swine hepatic lobules, including the formation of sinusoids and bile ducts. Based on our previous mouse model and the present pig models of induced sub-acute liver failure, the generation of auxiliary liver tissue using the lymph nodes as hepatocyte engraftment sites represents a potential therapeutic approach to supplement declining hepatic function in the treatment of liver disease.

During the past two decades, studies have provided evidence that age-associated shifts in the gut microbiome contributes to increased predisposition of aged individuals to certain diseases, including cardiovascular diseases, cancer, obesity, cancers, diabetes, and neurodegenerative diseases. Aging is a complicated process that affects physiological, metabolic, and immunological functions of the organism and thus is accompanied by inflammation and metabolic dysfunctions. The overall age-related increase in chronic inflammation and deterioration of systemic immune system led to coining the term "inflammaging". A direct causal role of the gut microbiome on host aging has been suggested by a number of studies using various experimental models.

The symbiotic co-existence between the host and microbiota is feasible due to the anatomical separation of microbial species from the host by a physical barrier. The intestinal barrier is responsible for adjusting metabolic homeostasis and systemic antimicrobial responses by detecting microbial-cell components and metabolites through its extensive repertoire of innate immune receptors. Relevant to aging, decline of the immune system in the aged intestinal epithelium have been suggested to contribute to age-onset dysbiosis. An important characteristic of age-onset dysbiosis is reduced microbiota diversity, which is suggested to lead to an expansion of distinct groups of bacteria. Concurrently, bacteria that is reported to be involved in maintenance of immune tolerance in the gut, such as Bifidobacteria and Lactobacilli, are found in reduced level in aged groups, whereas those that are found in increased levels, such as Enterobacteriaceae and Clostridium, are involved in infection and intestinal inflammation stimulation. Together, these studies suggest that the host immune system shapes not only the host's immune response to microbiome changes, but also the structure of the microbiome itself.

Cumulative evidence has implicated a close functional relationship between the immune system of the host and the microbiome, to an extent that the gut microbiome is important for proper development and expansion of intestinal mucosal and systemic immune system. Supporting the notion that the microbiome can directly shape the immune states of the host, the transcriptomic profile of African turquoise killifish guts derived from animals that received young or old gut microbiota transplants showed clear differences, especially in expression of immune-related genes.

Increased permeability of the intestinal barrier with age has been described across animal species, including worms, flies, mice and rats. Age-related deterioration of intestinal barrier function has been proposed to result in leakage of gut microbes into the systemic circulation, and ultimately lead to increased antigenic load and systemic immune activation. For example, age-associated remodeling of the gut microbiome in mice was shown to result in increased production of pro-inflammatory cytokines and intestinal barrier failure. In Drosophila, the age-related increase in Gammaproteobacteria was suggested to lead to increased intestinal permeability, inflammation, and mortality. The study showed that regardless of chronological age, intestinal dysbiosis serves as an indicator of age-onset mortality in flies.

Microbiome-derived short-chain fatty acids (SCFAs), including butyrate, propionate, acetate, and valerate, are important energy source for the epithelium and ultimately affects hypoxia-inducible factor-mediated fortification of the epithelial barrier. Interestingly, a decline in SCFA levels, including that of butyrate, were observed in aged humans, whereas centenarians presented with a rearrangement in the population of specific butyrate-producing bacteria. Microbiota-derived metabolites has also been reported to play a role in intestinal epithelial stem cell proliferation. For example, butyrate and nicotinic acid, both by-products of the gut microbiota, are involved in suppression and promotion of stem cell proliferation in the colon, respectively. In addition, microbiota-derived neurostimulators, including serotonin, glutamate, gamma-aminobutyric acid, have been reported to regulate proliferation of intestinal epithelial stem cells through the enteric nervous system. Other microbiota-derived metabolites have been shown to directly affect numerous systems of the host, although their functions in relation to host aging is in need of further investigation.

A large portion of mRNA in mammalian eukaryotic cells completes transcription in the nucleus and is then transported to the cytoplasm for translation and expression. When eukaryotic cells are stimulated or disturbed, the mature mRNA in cells cannot be translated into proteins immediately. These temporarily untranslated mRNA or translation-stalled mRNA then polymerize with RNA-binding proteins (RBPs) to form messenger ribonucleoprotein (mRNP) granules without a membrane structure, known as Cajal bodies, stress granules (SGs), processing bodies (P-bodies), RNA transport granules, or germ granules.

While mRNP granule types are complex and diverse, there are three commonalities between mRNP granules: first, mRNP granules usually contain non-translated or poorly translated mRNA, and these mRNA can re-enter polysome for translation after cellular adaption or environmental recovery. Second, different mRNP granules may contain the same mRNA or RBP and these components can be relocated from one mRNP granule to another granule. Third, different mRNP granules can interact dynamically, involving docking, fusion, and becoming another mRNP granule after maturation.

mRNP granules have a very important effect on mRNA function and cell signalling, and are also closely related to diseases. One of the most studied mRNP granules is SGs. SGs are a type of dynamic granular substance formed of mRNA of stagnant translation and RBPs in the cytoplasm of eukaryotic cells, the formation of which is stimulated by various stresses including oxidative stress, heat shock, hypoxia, or viral infection. It is an adaptive regulatory mechanism that protects cells from apoptosis under adverse conditions.

SGs have been identified in many biological processes and diseases. The assembly and disassembly of SGs determine further storage, translation remodelling, or degradation of untranslated mRNA, which affect cell death or survival under specific conditions. In cancer treatment, on the one hand, the formation of SGs can lead to cell survival and increase cell resistance to chemotherapeutic drugs. The combined use of drugs that inhibit SG formation or promote SG disassembly with chemotherapeutic drugs may alleviate drug resistance. On the other hand, some drugs may enhance the effects of chemotherapy by inducing SG-mediated cell apoptosis. Furthermore, the persistence of stress particles leads to chronic SG formation and irreversible pathogenesis, for example in neurodegeneration and aging.

It is therefore possible that targeting chronic SGs that inhibit the abnormal aggregation of related SGs or promote SG clearance may be a novel therapeutic strategy in neurodegenerative diseases and other chronic diseases. The formation and the biological functions of SGs are complex. Many questions need to be answered by research and the development of SG-targeting drugs. (1) Studies on SGs are largely confined to cell culture and C. elegans because of the absence of a suitable in vivo mammalian model. Ideally, a mouse model will be developed that can directly assess stress particles in living animals and more intuitively present direct associations between SGs, drugs, and diseases. (2) The side effects of the long-term administration of SG-interfering agents remain unclear. (3) Most SG contents are not the direct target of small molecules. So, the identification of druggable targets in SGs will reveal new biological functions and mechanisms of SG biology. Thus, SGs deserve more in-depth research.

Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm.

In this study, we examined associations between six major epigenetic measures of ageing and the prevalence and incidence of the leading causes of mortality and disease burden in high-income countries. DNAm GrimAge, a predictor of mortality, associated with the prevalence of COPD and incidence of various disease states, including COPD, type 2 diabetes, and cardiovascular disease. It was associated with death due to all-cause mortality and outperformed competitor epigenetic measures of ageing in capturing variability across clinically associated continuous traits. Higher values for DunedinPoAm, which captures faster rates of biological ageing, associated with the incidence of COPD and lung cancer. Higher-than-expected DNAm PhenoAge predicted the incidence of type 2 diabetes in the present study. Age-adjusted measures of DNAm Telomere Length associated with the incidence of ischemic heart disease. Our results replicate previous cross-sectional findings between DNAm PhenoAge and body mass index, diabetes, and socioeconomic position (in a basic model). We also replicated associations between DNAm GrimAge and heart disease.

In conclusion, using a large cohort with rich health and DNA methylation data, we provide the first comparison of six major epigenetic measures of biological ageing with respect to their associations with leading causes of mortality and disease burden. DNAm GrimAge outperformed the other measures in its associations with disease data and associated clinical traits. This may suggest that predicting mortality, rather than age or homeostatic characteristics, may be more informative for common disease prediction. Thus, proteomic-based methods (as utilised by DNAm GrimAge) using large, physiologically diverse protein sets for predicting ageing and health may be of particular interest in future studies. Our results may help to refine the future use and development of biological age estimators, particularly in studies which aim to comprehensively examine their ability to predict stringent clinically defined outcomes. Our analyses suggest that epigenetic measures of ageing can predict the incidence of common disease states, even after accounting for major confounding risk factors. This may have significant implications for their potential utility in clinical settings to complement gold-standard methods of clinical disease assessment and management.

Discerning the genetic factors that affect the aging process, in particular how they control lifespan, is one of the important yet unanswered questions in biology and evolution. Rodent species differ more than 10-fold in maximum lifespan, and long-lived rodents have been observed to show low susceptibility to certain age-related diseases. Therefore, analyses of their genomes could help discover genetic factors responsible for such diversity of lifespan. Motivated by this idea, an initial genome assembly of the naked mole rat (NMR), a rodent best known for its longevity (maximum lifespan of more than 35 years), was generated. It represented the first case of a mammalian genome being sequenced with the explicit purpose of providing insights into longevity. Analysis revealed several unique features and molecular mechanisms related to NMR phenotypes, such as cancer resistance, protein synthesis, visual function, etc.

The North American beaver has the second longest lifespan known for rodents, at more than 23 years. This species is famous for its ability to modify the environment by building complex dams and lodges, which sets them apart from other mammals. To date, two beaver genome assemblies have been reported, although extensive genome analyses have not been performed.

It should be noted that rodents have achieved long lives at least four times independently, and two contrasting combinations of longevity and body mass are recognized: i.e., species with large body mass and long lifespan (e.g., beaver and porcupine) and species with small body mass and long lifespan (e.g. naked mole-rat). Therefore, comparative analyses of these rodents and their closely related relatives that are characterized by small body mass and short lifespan could be useful for understanding how lifespan coevolved with body mass in rodents. It was proposed that the ability of organisms to effectively cope with both intrinsic and extrinsic stresses is linked with longevity.

With these goals in mind, we prepared high quality chromosome-level genome assemblies of the longest-lived rodents, the beaver and NMR. Our comparative genomic analyses reveal that amino acid substitutions at "disease-causing" sites are widespread in the rodent genomes and that identical substitutions in long-lived rodents are associated with common adaptive phenotypes, e.g., enhanced resistance to DNA damage and cellular stress. By employing a newly developed substitution model and likelihood ratio test, we find that energy metabolism and fatty acid metabolism pathways are enriched for signals of positive selection in both long-lived rodents.

Increasing evidence has pointed to the interactions between genetics, epigenetics, and environmental factors in the aging process. Over the last decade, there has been a growing body of research in identifying genetic and epigenetic biomarkers of aging to decipher the molecular mechanisms underpinning disease susceptibility. For example, the genome-wide association studies (GWAS) have identified genetic loci associated with longevity and several aging-related diseases. As aging is a multifactorial process determined by the dynamic nature of static genetics as well as stochastic epigenetic variation and transcriptomics regulation, both DNA methylation and gene expression have emerged as promising hallmark for understanding the aging process and its associated diseases.

Numerous estimators have been developed to predict human aging from DNA methylation data. While the first generation DNA methylation age estimators including Horvath's clock and Hannum's clock were developed based on chronological age, the second generation DNA methylation age estimators were obtained by optimizing the prediction error on phenotypic age derived from clinical attributes associated with mortality and morbidity. This includes PhenoAge and GrimAge which aim to improve prediction of aging related outcomes (e.g., time-to-death, time-to-disease for cancer, Alzheimer's disease, and cardiovascular disease).

In addition to DNA methylation, changes in gene expression have been shown to be associated with aging and aging-related outcomes. Specifically, 56 consistently over-expressed and 17 genes consistently under-expressed with chronological age were identified by performing a meta-analysis on 27 microarray datasets from mice, rats, and human subjects. A closely related work was the development of the GenAge database of aging-related genes, including 307 genes potentially related to human aging.

Unlike DNA methylation in which several user-friendly software and computer programs are available for predicting epigenetic age across different tissues, there were limited transcriptional age predictors and the existing predictors have several pitfalls. First, most of the human transcriptional age predictors were developed based on microarray data and/or limited to only a few tissues. Second, the only predictor constructed using RNA-Seq data was derived based only on fibroblast data. To date, transcriptional studies on aging using RNA-Seq data across different human tissues was limited. Recognizing the gap in existing research of transcriptional aging based on RNA-Seq data, the aim of this study was twofold, first to identify common age-related genes across tissues; second to construct tissue-specific transcriptional age calculators for understanding how gene expression changed with age in different human tissues.

Based on our results, we introduce RNAAgeCalc, a versatile across-tissue and tissue-specific transcriptional age calculator. By performing a meta-analysis of transcriptional age signature across multi-tissues using the GTEx database, we identify 1,616 common age-related genes, as well as tissue-specific age-related genes. Based on these genes, we develop new across-tissue and tissue-specific age predictors. We show that our transcriptional age calculator outperforms other prior age related gene signatures as indicated by the higher correlation with chronological age as well as lower median and median error. Our results also indicate that both racial and tissue differences are associated with transcriptional age. Furthermore, we demonstrate that the transcriptional age acceleration computed from our within-tissue predictor is significantly correlated with mutation burden, mortality risk, and cancer stage in several types of cancer from the TCGA database, and offers complementary information to DNA methylation age.

Neurons are composed of axons, i.e., long fiber-like extensions that transmit signals to other cells. Many of them are surrounded by a myelin sheath, a thick fatty layer that protects them and helps to transfer stimuli rapidly. Without myelin, the functional capacity of neurons - and therefore of the whole nervous system - is limited and neurons can easily degenerate. Multiple sclerosis (MS) is one of the diseases associated with myelin sheath degradation. MS patients suffer successive episodes of demyelination resulting in a progressive loss of function of their nervous system. Remyelination of the axons can prevent this.

Intact myelin sheaths are a prerequisite for the healthy functioning of the peripheral and central nervous systems. If the peripheral nervous system (PNS) is damaged, in an accident involving injury to the arms or legs for example, the axons and their myelin sheaths can recover relatively well. However, the central nervous system (CNS) is completely different in this regard as there is no efficient restoration of the axons and therefore of the myelin sheath after a lesion. This means that CNS injuries usually result in permanent paralysis - as in the case of MS when loss of myelin leads to axon degeneration. Further, the capacity of the body to remyelinate decreases dramatically with age.

Researchers recently investigated how remyelination occurs in both peripheral and central nervous systems of mice. The neuroscientists identified a protein called eEF1A1 as a key factor in the process and found that eEF1A1 activated by acetylation prevents the remyelination process, but if eEF1A1 is deactivated by deacetylation, myelin sheaths can be rebuilt. The protein that deacetylates eEF1A1 is the enzyme called histone deacetylase 2 (HDAC2).

The researchers decided to try to control this process by boosting HDAC2 activity and its synthesis in cells. This was achieved by using the active substance theophylline, which has long been used in the treatment of asthma. In a mouse model, the use of theophylline over a period of four days resulted in significant recovery. Restoration of myelin sheaths was particularly impressive in the PNS, where they recovered completely. Regeneration also improved in the CNS, as there was rapid and efficient rebuilding of myelin sheaths in both young and old mice. A low dose of the active substance was sufficient to trigger the improvements - a big plus with regard to the known side effects of theophylline, which occur at higher doses.

One of the major challenges to healing after the kind of nerve injury resulting from stroke or spinal cord damage is the formation of a glial scar. A glial scar is formed by cells and biochemicals that knit together tightly around the damaged nerve. In the short term, this protective environment shields the nerve cells from further injury, but in the long term it can inhibit nerve repair.

About two decades ago, scientists discovered that a natural enzyme known as chondroitinase ABC - produced by a bacterium called Proteus vulgaris - can selectively degrade some of the biomolecules that make up the glial scar. By changing the environment around the damaged nerve, chondroitinase ABC has been shown to promote regrowth of nerve cells. In animal models, it can even lead to regaining some lost function. But progress has been limited by the fact that chondroitinase ABC is not very stable in the places where researchers want to use it. "It aggregates, or clumps together, which causes it to lose activity. This happens faster at body temperature than at room temperature. It is also difficult to deliver chondroitinase ABC because it is susceptible to chemical degradation and shear forces typically used in formulations."

Various teams have experimented with techniques to overcome this instability. Some have tried wrapping the enzyme in biocompatible polymers or attaching it to nanoparticles to prevent it from aggregating. Others have tried infusing it into damaged tissue slowly and gradually, in order to ensure a consistent concentration at the injury site. But all of these approaches fail to address the fundamental problem of instability. Now researchers tried a new approach: they altered the biochemical structure of the enzyme in order to create a more stable version. In the end, the team ended up with three new candidate forms of the enzyme that were then produced and tested in the lab. All three were more stable than the wild type, but only one, which had 37 amino acid substitutions out of more than 1,000 possible substitution locations, was both more stable and more active.

"The wild type chondroitinase ABC loses most of its activity within 24 hours, whereas our re-engineered enzyme is active for seven days. This is a huge difference. Our improved enzyme is expected to even more effectively degrade the glial scar than the version commonly used by other research groups." The next step will be to deploy the enzyme in the same kinds of experiments where the wild type was previously used.

Impaired cerebrovascular function, a universal feature of aging, is a biomarker for increased risk of Alzheimer's disease (AD), and is one of the earliest detectable changes in the pathogenesis of AD. Indeed, chronic cerebral hypoperfusion typically develops nearly a decade prior to cognitive decline and precedes the presence of pathological hallmarks of AD, including brain atrophy and accumulation of β-amyloid and pathogenic tau. In accordance with the two-hit vascular hypothesis of AD, these observations suggest that early age-associated cerebrovascular dysfunction may trigger the development of cerebrovascular pathology, driving cognitive impairment and accelerating the pathogenesis of neurological diseases of aging, including AD. Thus, cerebrovascular dysfunction may represent one of the earliest and most therapeutically addressable biological pathways under-lying age-related cognitive impairment and neurological disease.

Research from our lab and others showed that the mechanistic/mammalian target of rapamycin (mTOR) drives several different aspects of cerebrovascular dysfunction in models of AD and vascular cognitive impairment and dementia (VCID), including blood-brain barrier (BBB) breakdown, cerebral hypoperfusion, reduced cerebrovascular reactivity, and impaired neurovascular coupling. We recently established that mTOR drives age-related cerebrovascular dysfunction in 34-month-old aged rats devoid of overt pathology or disease. Cerebral blood flow deficits in aged rats were associated with microvascular rarefaction, synaptic loss, impaired neuronal network activation, and spatial learning and memory impairments. Chronic mTOR attenuation via rapamycin preserved cerebrovascular function and microvascular integrity, improved synaptic integrity and neuronal network activation throughout aging, and negated age-related cognitive decline in aged rats. These recent results indicate that in addition to driving cognitive and cerebrovascular deficits in models of AD and VCID, mTOR underlies the etiology of age-associated cerebrovascular and neuronal dysfunction during normative aging.

Terminally differentiated postmitotic cells such as mature neurons and glia are long-lived and must cope with the accumulation of damage over the course of an animal's lifespan. The mechanisms used by such long-lived cells to deal with aging-related damage are poorly understood. The brain of the fruit fly Drosophila melanogaster is an ideal context to examine this since the fly has a relatively short lifespan and the adult fly brain is nearly entirely postmitotic with well understood development and excellent tools for genetic manipulations.

Polyploidy can confer an increased biosynthetic capacity to cells and resistance to DNA damage induced cell death. Several studies have noted neurons and glia in the adult fly brain with large nuclei and in some cases neurons and glia of other insect species in the adult central nervous system (CNS) are known to be polyploid. Rare instances of neuronal polyploidy have been reported in vertebrates under normal conditions and even in the CNS of mammals.

Polyploidization is employed in response to tissue damage and helps maintain organ size. Therefore, polyploidy may be a strategy to deal with damage accumulated with age in the brain, a tissue with very limited cell division potential. Here we show that polyploid cells accumulate in the adult fly brain and that this proportion of polyploidy increases as the animals approach middle-age. We show that multiple types of neurons and glia which are diploid at eclosion which become polyploid specifically in the adult brain. We have found that the optic lobes of the brain contribute to most of the observed polyploidy. We also observe increased DNA damage with age, and show that inducing oxidative stress and exogenous DNA damage can lead to increased levels of polyploidy. We find that polyploid cells in the adult brain are resistant to DNA damage-induced cell death and propose a potentially protective role for polyploidy in neurons and glia in adult Drosophila melanogaster brains.

The world population is aging rapidly. Organ transplantation is the treatment of choice for patients with irreversible end-stage organ failure. The supply of organs, however, is limited, resulting in prolonged waiting times with many patients dying or becoming too ill to be eligible for transplantation. Currently, the most obvious strategy with potential for closing the gap between demand and supply would be to enable the use of organs from older deceased donors that currently are frequently discarded.

Aging is associated with increased senescent cell burden that is linked to chronic, low grade, sterile inflammation. Increased levels of cytokines, including IL-6, IFN-γ, and TNF-α, contribute to the pro-inflammatory secretome of senescent cells, termed the senescence-associated secretory phenotype or SASP. Damage-associated molecular patterns (DAMPs), which include mitochondrial DNA (mt-DNA), also increase with aging. Relationships among senescent cell accumulation, mt-DNA, the SASP, outcomes of transplantation in clinically relevant disease models, and the potential to mitigate injury and augmented immunogenicity of older organs by targeting senescent cells have so far not been tested. However, recent studies propose that circulating mitochondria and mt-DNA might mediate early allograft dysfunction.

Ischemia and reperfusion injury (IRI) is characterized by initial tissue hypoxia with metabolic changes and subsequent further damage with the reintroduction of oxygen and elevated shear forces during reperfusion. Local tissue injury is followed by a systemic sterile inflammatory response, mediated by DAMPs including mt-DNA.

Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. IRI induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflammaging and present senolytics as a potential approach to improve transplant outcomes and availability.

The boxer Muhammad Ali is quoted as saying that: Age is whatever you think it is. You are as old as you think you are. Similarly, author Mark Twain joked that: Age is just a state of mind. I say it is more about the state of your body. Clearly, there is a wide divergence of opinions about the proper definition of true age, all of which are quite distinct from the number of times you circled the sun. In fact, recent work indicates that economic behavior is highly correlated with how old people feel versus their chronological age. The pertinent question here is whether actuarial science can contribute yet another age metric, one that is consistent with heterogeneous mortality and known mathematical theories of aging. This paper argues that the answer is yes.

This paper develops a computational framework for inverting Gompertz-Makeham mortality hazard rates, consistent with compensation laws of mortality for heterogeneous populations, to define a longevity-risk-adjusted global (L-RaG) age. To illustrate its salience and possible applications, the paper calibrates and presents L-RaG values using country data from the Human Mortality Database (HMD). Under this approach, the data indicate that for a male at chronological age 55, the gap in L-RaG ages between high-mortality (e.g. Russia) and low-mortality countries (e.g. Sweden), can be as high as 20 years: a 55-year-old Swedish male has an L-RaG age of 48, whereas a 55-year-old Russian male is closer in L-RaG age to 67. Stated differently, using the language of risk-adjusted benchmarks, your true age depends on where you live.

Frailty is largely associated with sarcopenia, aging-related loss of muscle mass and function, characterised by a progressive and degenerative loss of skeletal muscle mass, quality, and strength during aging. Sarcopenia affects 5-13% of 60-70 year olds and up to 50% of people over 80. The role of microRNAs (miRNAs, miRs) as epigenetic modifiers in regulating loss of muscle mass and function has become increasingly recognised. miRs are short, non-coding RNAs which regulate the expression of approximately two thirds of human genes.

In skeletal muscle, miRs have been demonstrated to control multiple biological processes, including development, regeneration, and aging. A number of miRs are involved in the regulation of muscle protein synthesis, that target regulators involved maintaining the balance between muscle atrophy and hypertrophy, and including regeneration of skeletal muscle. Early studies in humans demonstrated differential expression of miRs in skeletal muscle during aging. We and others have demonstrated the role of miRs in aging-associated processes in skeletal muscle, such as satellite cell senescence and inflammation.

Bioinformatic analyses of non-coding RNAs and transcripts in human and rodent muscle during aging have identified miR-181a as a potentially key regulator of muscle mass and function during aging. In skeletal muscle, miR-181a appears to be the predominant miR-181 family member in skeletal muscle affected by aging and has been suggested as biomarker of muscular health. miR-181 has also been demonstrated to be upregulated in muscle during exercise and predicted to regulate transcription factors and co-activators involved in the adaptive response of muscle to exercise. Based on computer simulation models, miR-181a was predicted to regulate muscle atrophy and hypertrophy through its target genes: HOXA11 by inhibiting MYOD, and SIRT1, through regulating FoxO3 signalling. Indeed, we and others confirmed these as miR-181a direct targets.

More recently, miR-181 family of miRs gained more attention due to their regulation of processes associated with mitochondrial dynamics. Mitochondrial dysfunction is one of the hallmarks of aging. During aging, skeletal muscle is characterised by a loss of mitochondrial content and disrupted mitochondrial turnover, particularly in sedentary individuals. A number of studies to date suggest that miR-181a may be a global regulator of mitochondrial dynamics, redox homeostasis, and potentially energy balance of the whole organism.

Researchers have found a treatment that increases the speed of nerve regeneration by three to five times, which may one day lead to much better outcomes for trauma surgery patients. Peripheral nerve injury occurs in about three per cent of trauma victims. The slow nature of nerve regeneration means that often muscles atrophy before the nerve has a chance to grow and reconnect. That's where conditioning electrical stimulation (CES) comes in. The process involves electrically stimulating a nerve at the fairly low rate of 20 hertz for one hour. A week after the CES treatment, nerve surgery is done, and the nerves grow back three to five times faster than if the surgery was done without CES.

In their latest work on CES, researchers examined animal models with foot drop, a common injury that affects patients' quality of life by impeding their ability to walk normally. Previously, the only treatments for foot drop were orthotics, that affect a patient's gait, or surgery. Researchers performed a distal nerve transfer in which a nerve near the damaged one was electrically stimulated, then a week later a branch of the nerve was cut and placed near the target of the non-functioning nerve. The newly transferred nerve would then be primed and ready to regrow, at a much faster rate, into the muscles that lift the foot. Researchers hopes to bring the information gained from examining nerve transfers in the leg - a difficult body part for nerve regrowth due to the vast area the nerve must cover - to clinical trials within the next year or two.