Sirtuins, comprising a group of evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent proteins, beneficially regulate lifespan and cellular senescence. In mammalian cells, seven different sirtuin proteins have been identified (SIRT1-7). SIRT1 and SIRT2 are present in both the nucleus and cytoplasm; SIRT3, SIRT4 and SIRT5 are exclusively found in mitochondria, and SIRT6 and SIRT7 are thought to be located in the nucleus. Notably, in response to stress, SIRT6 localizes to cytoplasmic stress granules, suggesting that SIRT6 is not exclusively a nuclear protein. Sirtuins are involved in a broad range of physiological processes, including genome stability, energy metabolism, aging, tumorigenesis, and cardiovascular biology, via their regulation of key protein activities.

Among sirtuin family members, sirtuin 6 (SIRT6) is of particular interest and has gained more attention due to its distinctive enzymatic activities; for example, SIRT6 catalyzes deacetylation and mono-ADP-ribosylation and exhibits long-chain fatty acid (FA) deacylase activity. These enzymatic activities indicate that SIRT6 is closely related to cellular biological processes, such as DNA repair, genome stability, inflammation, and metabolic homeostasis. Studies have revealed that dysregulation of SIRT6 activity leads to the onset and development of many diseases, including but not limited to metabolic diseases, cardiovascular diseases (CVDs), cancers, and neurodegenerative diseases.

The essential roles of SIRT6 in regulating chromatin and nuclear-cytoplasmic signaling pathways important for cellular homeostasis have been well characterized. In terms of genome stability, SIRT6 enhances DNA repair and maintains telomere integrity by regulating DNA repair and chromatin-associated factors, such as PARP1, DDB2, SNF2H and WRN. With respect to cellular metabolism, SIRT6 regulates multiple metabolic processes, including glycolysis, gluconeogenesis, insulin secretion, lipid synthesis, lipolysis, and thermogenesis, mainly by regulating the multiple transcriptional activities of HIF1α, FOXO proteins, and the PPAR family of transcription factors.

In addition, SIRT6 maintains an appropriate inflammatory response by regulating the TNF-α and NF-κB signaling pathways. These functions can influence cellular senescence and aging-related diseases, including CVDs, cancer, and neurodegenerative diseases. Therefore, studying the biological functions of SIRT6 in different diseases is valuable and helpful for the identification of highly specific SIRT6 cellular targets. With a deeper understanding of SIRT6, certain SIRT6 regulatory compounds have been identified, offering novel and promising therapeutic options for aging-related diseases.

Today, the U.S. Food and Drug Administration approved Rebyota, the first fecal microbiota product approved by the agency. Rebyota is approved for the prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older. It is for use after an individual has completed antibiotic treatment for recurrent CDI. Clostridioides difficile (C. difficile) is a bacterium that can cause CDI, a potentially life-threatening disease resulting in diarrhea and significant inflammation of the colon. In the United States, CDI is associated with 15,000-30,000 deaths annually.

The intestinal tract contains millions of microorganisms, often referred to as the "gut flora," or "gut microbiome." Certain situations, such as taking antibiotics to treat an infection, may change the balance of microorganisms in the gut, allowing C. difficile to multiply and release toxins causing diarrhea, abdominal pain and fever, and in some cases, organ failure and death. Other factors that can increase the risk for CDI include age older than 65 years, hospitalization, a weakened immune system and a previous history of CDI. After recovering from CDI, individuals may get the infection again - often multiple times-a condition known as recurrent CDI. The risk of additional recurrences increases with each infection and treatment options for recurrent CDI are limited. The administration of fecal microbiota is thought to facilitate restoration of the gut flora to prevent further episodes of CDI.

Rebyota is administered rectally as a single dose. Rebyota is prepared from stool donated by qualified individuals. The donors and the donated stool are tested for a panel of transmissible pathogens, however, as Rebyota is manufactured from human fecal matter, it may carry a risk of transmitting infectious agents. In addition, Rebyota may contain food allergens; the potential for the product to cause adverse reactions due to food allergens is unknown. The safety of Rebyota was assessed from two randomized, double-blind, placebo-controlled clinical studies and from open-label clinical studies conducted in the United States and in Canada.

The effectiveness of Rebyota was evaluated in an analysis of data from a randomized, double-blind, placebo-controlled, multicenter study. The analysis included 177 adults who received one dose of Rebyota and 85 who received one dose of placebo in this study. It also incorporated success rates from a different placebo-controlled study in which 39 adults received one dose of Rebyota and one dose of placebo and 43 adults received two doses of placebo. Success in preventing recurrent CDI was defined as the absence of CDI diarrhea within 8 weeks of administration of Rebyota or placebo. In a statistical analysis that took into account both studies, the overall estimated rate of success in preventing recurrent CDI through 8 weeks was significantly higher in the Rebyota group (70.6%) than in the placebo group (57.5%).

Currently, various treatment strategies are being investigated to slow or reverse ageing-associated diseases; unfortunately, no preventive or effective treatments have yet been identified. The major challenge associated with this process, thus far, remains the lack of highly efficient disease models of neurodegeneration. In this review, various ageing hallmarks were discussed, most of which have been associated with neurodegenerative diseases.

We propose that future studies of neurodegenerative diseases should focus on these hallmarks of ageing and that ageing models should be developed that show neurodegenerative disease phenotypes. Although this paper primarily focused on DNA damage, cellular senescence, and mitochondrial dysfunction, studies examining the relationships between the nucleus and mitochondria would reveal the mechanistic links between ageing and neurodegeneration. Other hallmarks, such as proteostasis, epigenetic deregulation, and telomerase inactivation, are also important. The loss of proteostasis results in proteasomal and autophagy defects in both Alzheimer's disease and Parkinson's disease, resulting in inflammation and senescence. Metabolic dysfunction has been shown to be associated with mitochondrial dysfunction, oxidative stress, and NAD+ levels.

Although cross-talk between inflammatory pathways and neurodegeneration has been recognized for the past two decades, very few therapeutic strategies have emerged from this line of research due to the lack of a high-throughput screening platform. To harness the therapeutic potential of inflammatory pathways, a better understanding of the neuroprotective role played by TNF-α and NF-κB remains necessary, and new models must be developed that are able to recapitulate microglia-induced neurodegenerative phenomena in vivo. However, neurodegenerative diseases are complex to decipher, and their central mechanisms are further complicated by the interactions that occur between genetic and environmental factors, which drive disease progression. A single-pathway-oriented therapeutic intervention might not be sufficient for the treatment of these complex disease, although combination therapies may be successful.

Identifying functional links between neurodegenerative diseases and ageing hallmarks could reveal new therapeutic avenues. A multi-target, evidence-based approach associated with non-pharmacological approaches, such as lifestyle modifications, may slow neurological disease progression in older individuals.

Here we show that hundreds of axons around each amyloid plaque develop spheroids and, rather than being retraction bulbs from degenerating axons, these structures are stable for extended periods of time and could therefore have an ongoing detrimental effect on neuronal connectivity. Given the similarity in the morphology, organelle and biochemical content of plaque-associated axonal spheroids (PAASs) in mice and humans, it is probable that, in humans, these are also stable structures that could disrupt neural circuits for extended intervals.

To better understand the effect of PAASs on axonal function, we implemented in vivo Ca2+ and voltage imaging in individual cortical axons and cell bodies. Both Ca2+ and voltage imaging revealed that a substantial proportion of axons in a mouse model of Alzheimer's disease (AD) had disrupted AP conduction and an overall increase in the threshold for action potential propagation manifested by conduction blockades. This was due to the presence of axonal spheroids and was shown to be correlated with their size. The finding that larger PAASs caused more severe conduction blocks was consistent with computational modelling showing that PAASs resemble electrical capacitors that function as current sinks, and that PAAS size is a major determinant of the degree of conduction defects. Together, our data suggest that the large number of amyloid deposits present in the AD brain have the potential to substantially affect neural networks by widespread disruption of axonal connectivity.

Mechanistically, we found that enlarged LAMP1-positive vesicles (ELPVs) - which probably include multivesicular bodies (MVBs), endolysosomes, and autolysosomes - accumulate within axonal spheroids and that their presence is correlated with spheroid size. Moreover, we found an increased presence of ELPVs within spheroids in older Alzheimer's model mice and in more severely impaired human patients with AD, indicating that ELPV accumulation may be a key feature of disease progression. MVBs are crucial intermediate organelles that evolve through the maturation of endosomes and fuse with autophagosomes and lysosomes. Thus, dysregulation in MVB biogenesis has the potential to affect the normal generation of fusion vesicles.

Spheroid growth was also mechanistically linked with Pld3 - a potential Alzheimer's-disease-associated risk gene that encodes a lysosomal protein that is highly enriched in axonal spheroids. Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function. Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer's disease, independent of amyloid removal.

Hematopoietic stem cell (HSC) pools are positioned at the hematopoietic hierarchical apex and sustain multi-lineage hematopoiesis throughout the mammalian lifetime. They can do so by maintaining relative quiescence, self-renewal, and infrequent divisions during steady-state hematopoiesis. These critical processes are governed by ancillary cells in so-called stem cell niches, which include endothelial and mesenchymal cells in the mammalian hematopoietic system. Recent findings implicate resident innate and adaptive immune cells in the homeostatic regulation of stem cells. In particular, macrophages and regulatory T cells are established regulators of hematopoietic stem cells under homeostatic conditions.

The contribution of neutrophils, the most abundant innate immune cell in the human bone marrow, to homeostatic stem cell regulation, however, has remained largely elusive. This is mainly due to the lack of models fulfilling the experimental paradigm for defining HSC-regulating cells, which is (long-term) specific depletion of a candidate regulatory cell, followed by rigorous examination of HSC function. Existing models of neutropenia either induce transient, short-term reduction of neutrophil levels and/or employ genetic strategies that target HSCs themselves, precluding conclusions on the effect of neutropenia on long-term HSC biology.

Here, utilizing a mouse model of profound, sustained, and specific depletion of mature myeloid cells (neutrophils and eosinophils), we demonstrate that HSC integrity and function are conserved, implicating divergent responses of stem and progenitor cells to compensate for myeloid lineage shortages. Unexpectedly, the depletion of myeloid cells attenuated inflammatory signaling in stem cells and their niches via the reduction of natural killer (NK) cell numbers and activation status and abrogated the loss of HSC function in serial transplantation, identifying a neutrophil-NK cell axis as a critical determinant of the functional decline of the hematopoietic system.

Mitochondria are small organelles that play an essential role in the energy production of eukaryotic cells. Here, we analyzed the mitochondrial genomes of 532 whole-genome sequencing samples from cancers and normal clonally expanded single cells. We have shown that the speed with which mitochondria in normal tissues accumulate somatic mutations with age was similar between different tissues. By comparing normal cells with cancer from the same tissue, we have also shown that most mitochondrial mutations in cancer are the result of normal mutagenesis and that treatment perturbations do not strongly impact the mitochondrial mutation load.

In general, cancers and treatment did not have a large effect on the mitochondrial genomes. Chemotherapy, for example, did not result in large observable increases in mitochondrial mutation loads both in vivo and in vitro, even though it can lead to large increases in nuclear mutation loads. This suggests that the relation between cancer and mitochondria is not dependent on mitochondrial mutations. One possible explanation for the limited effect of cancer and its treatments is that the mitochondrial DNA damage they cause might be resolved by cells clearing their damaged mitochondria.

Long term high fat diets (HFD) promote skin aging pathogenesis, but detailed mechanisms remain unclear especially for inflammaging, which has recently emerged as a pathway correlating aging and age-related disease with inflammation. p16INK4a (hereafter termed p16) inhibits the cell cycle, with p16 deletion significantly inhibiting inflammaging. We observed that HFD-induced p16 overexpression in the skin. Therefore, we investigated if p16 exacerbated inflammaging in HFD-induced skin and also if p16 deletion exerted protective effects against this process.

Eight-week-old double knockout (KO) ApoE-/-p16-/- mice and ApoE-/- littermates were fed HFD for 12 weeks and their skin phenotypes were analyzed. We measured skin fibrosis, senescence-associated secretory phenotype (SASP) levels, and integrin-inflammasome pathway activation using histopathological, RNA-sequencing (RNA-seq), bioinformatics analysis, and molecular techniques.

We found that HFD contributed to inflammaging in the skin by activating the NLRP3 inflammasome pathway, increasing inflammatory infiltration, and promoting apoptosis by balancing expression between proapoptotic and antiapoptotic molecules. p16 knockout, when compared with the ApoE-/- phenotype, inhibited skin fibrosis by ameliorating inflammatory infiltration and proinflammatory factor expression via Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and also alleviated inflammaging skin progress induced by HFD in the ApoE-/- mouse model. RNA-seq showed that p16 KO mice inhibited both integrin-inflammasome and NF-κB proinflammatory pathway activation.

In conclusion, p16 deletion or p16 positive cell clearance could be a novel strategy preventing long term HFD-induced skin aging.

Low density lipoprotein cholesterol (LDL-C) is a well established causal risk factor for the development of atherosclerosis and cardiovascular disease. High levels of LDL-C consistently predict a risk of future atherosclerotic cardiovascular events in a variety of populations throughout the world. Also, many randomised controlled trials of treatment with lipid lowering agents have clearly shown that lowering LDL-C levels reduces the risk of atherosclerotic cardiovascular events in the future.

Because lowering levels of LDL-C reduces cardiovascular disease outcomes, the general perception is that high levels of LDL-C are associated with an increased risk of mortality but low levels are not. Studies on the association between LDL-C levels and the risk of all cause mortality, however, have provided conflicting results, with some studies showing a counterintuitive inverse association (lower mortality with increasing levels of LDL-C) and some showing no association. Most of these studies were conducted in individuals aged 65 and older, and in historical population based cohorts.

In this study, we determined the association between levels of LDL-C and the risk of all cause and cause specific mortality. Among 108,243 individuals aged 20-100, 11,376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL), the multivariable adjusted hazard ratio for all cause mortality was 1.25 for individuals with LDL-C concentrations of less than 1.8 mmol/L (under 70 mg/dL) and 1.15 for LDL-C concentrations of more than 4.8 mmol/L (over 189 mg/dL).

The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction.

Adult-onset neuronal ceroid lipofuscinosis (ANCL) is an inherited neurodegenerative disease with progressive neuronal dysfunction characterized by neuronal death and lipofuscin deposition in the neuronal or non-neuronal lysosomes. Although mutations in CSPα, encoded in the human DNAJC5 gene, are known to be associated with ANCL, the pathogenic mechanisms involved remain unknown. The most well-studied function of CSPα is its cytoplasmic chaperone function. CSPα is abundant in presynaptic vesicles, interacting with HSC70 to ensure correct protein folding. Mutant CSPα causes loss of palmitoylation, mislocalization, and aggregation of CSPα, which then triggers a series of reactions and destabilizes key proteins related to its function, such as synaptic SNAP-25 proteins and PPT1 proteins. Although the exact mechanism is unknown, certain changes in these proteins contribute to NCL.

In numerous animal and human studies, defects in CSPα have been shown to cause neurodegeneration. In addition to ANCL, Alzheimer's disease, Parkinson's disease, FTD, and Huntington's disease have been shown to be associated with CSPα. Although the mechanisms of these neurodegenerative diseases have not been fully explained, neurodegenerative diseases are often associated with protein misfolding. Further studies have revealed that CSPα is essential for transporting misfolded proteins. CSPα has been shown to be associated with lysosomal degradation. Inadequate lysosomal degradation can lead to abnormal membrane flow and misfolded protein entry into endolysosomes, thus leading to error-prone protein accumulation. Additionally, CSPα has been shown to be involved in misfolding-associated protein secretion, endosomal microautophagy, and unfolded protein response processes, which are known to play important roles in maintaining the stability of misfolded proteins. However, all the relevant mechanisms researches are not detailed enough, and more evidence is required to reveal the deeper molecular mechanisms.

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence.

We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)-dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21 knockout model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement.

Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.

Melanoma is an aggressive type of skin cancer. Ten years ago, metastatic melanoma was almost certainly a death sentence within a year after diagnosis. "Ten years ago, melanoma had such a bad prognosis that I would be seeing an entirely new patient population every year - but now I've been seeing some patients for ten years. This is largely due to the discovery of immunotherapy, which has revolutionized treatment for melanoma. But we still see that about half of the people diagnosed with metastatic melanoma succumb within five years, so we're still not where we want to be - not at all."

TIL stands for tumor-infiltrating lymphocytes: immune cells, T cells in this case, that have entered the tumor. The body trains these T cells to recognize and then kill foreign invaders, such as tumor cells. The presence of T cells in a tumor is a good sign, because it means that the immune system has recognized the tumor as a foreign entity and wants to attack and destroy it. Many tumors, however, do not contain enough potent T cells. TIL therapy aims to multiply the patient's T cells, which are isolated from one of the tumor sites, into a huge army consisting of billions of T cells.

Researchers started an international trial in 2014: the TIL trial, which compared TIL therapy to standard immunotherapy with the checkpoint inhibitor ipilimumab. The results of the TIL trial have now been presented. In almost half (49%) of the patients with metastatic melanoma who received TIL therapy, the metastases had decreased in size. In 20% of patients, the metastases had even disappeared completely. This also proved to be the case in patients who had already received prior treatment at the time of their participation in the trial. These percentages were significantly higher compared to those seen in the patient group receiving standard immunotherapy (ipilimumab). In the ipilimumab group, metastases had decreased in size in 21% of patients, and in 7%, the metastases had disappeared completely.

The progression-free survival, the percentage of patients who do not experience disease progression after a specified time period, was 53% after six months for patients receiving TIL therapy, and 21% in the control group (ipilimumab). At a median follow-up time of 33 months for all patients, the median progression-free survival of patients who had received TIL therapy was significantly better (7 months) than that of patients treated with ipilimumab (3 months).

Learning a new task, mastering a musical instrument or being able to adapt to the constantly changing environment are all possible thanks to the brain's plasticity, or its ability to modify itself by rearranging existing neural networks and forming new ones to acquire new functional properties. This also helps neural circuits to remain healthy, robust and stable. To better understand brain plasticity, researchers used mouse models to investigate how brain cells build connections with new neurons born in adult brains.

The researchers discovered that levels of oxytocin increase in the olfactory bulb, peaking at the time the new neurons incorporate themselves into neural networks. Using viral labeling, confocal microscopy, and cell-type specific RNA sequencing, the team discovered that oxytocin triggers a signaling pathway - a series of molecular events inside cells - that promotes the maturation of synapses, that is, the connections of newly integrated adult-born neurons. When the researchers eliminated the oxytocin receptor, the cells had underdeveloped synapses and impaired function.

"Our findings suggest that oxytocin drives development and synaptic integration of new neurons within the adult brain, directly contributing to adaptability and circuit plasticity. Oxytocin is normally present in our brain, so if we understand how to turn it on or off or mobilize it, we can help keep our circuit connections healthy by promoting the growth of underdeveloped connections or strengthening new ones. Our findings also suggest that oxytocin could promote the growth of new neurons to repair damaged tissue. Further studies are needed to explore these possibilities."

Endothelial dysfunction, a leading cause of abnormal vasodilation, is the basis of many cardiovascular diseases. Improving endothelial function has been shown to be beneficial in the prevention and treatment of hypertension and coronary heart disease (CHD). However, to date, little is known about the effects of existing methods on the prevention of endothelial dysfunction. Therefore, exploring the mechanism of endothelial dysfunction may be beneficial in the development of more effective therapeutic targets. Endothelial nitric oxide synthase (eNOS) is a vital enzyme required for NO synthesis in endothelial cells and is the primary regulator of homeostasis and vascular tone. A decline in eNOS expression often leads to increased vascular tension and decreased local blood perfusion, which are responsible for the development of many cardiovascular diseases.

Sterile inflammation has been shown to occur with aging. This type of inflammatory response is due to immune dysfunction and is closely associated with aging-related organ dysfunction. Evidence suggests that the increase in pro-inflammatory factors caused by sterile inflammation reduces vascular eNOS expression and NO production, leading to vasodilation dysfunction and ultimately aging-related cardiovascular diseases. However, the mechanisms involved in the regulation of age-related aseptic inflammation need further exploration.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a newly discovered component of the innate immune system. The cGAS acts as a cytoplasmic DNA sensor, and its activation leads to activation of the downstream target STING, and subsequent phosphorylation of interferon regulatory factor 3 (IRF3). The main targets of IRF3 are inflammatory genes such as interferon-β (IFNβ), Ifit1, Ifit2, Ifit3, and MCP-1. Increased transcription of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and IL-6 eventually lead to sterile inflammation. Sterile inflammation is similar to inflammation that appears during infection and may be responsible for tissue injury.

A decline in endothelial function, up-regulation of p53, p21, and p16 expression, and activation of the cGAS-STING pathway were observed in aging mice. Inhibition of cGAS was found to improve endothelial function and reverse the increased expression of aging markers. Our in vitro data demonstrated that D-galactose induced a decrease in eNOS expression and cell senescence, which could be partly reversed by cGAS inhibitor, STING inhibitor, siRNA-cGAS and siRNA-STING treatment. Higher expression levels of cGAS, STING, and p-IRF3 were observed in aged human aortic intima tissue compared to young aortic intima tissue. Our study demonstrated that activation of the cGAS-STING pathway played a vital role in aging-related endothelial dysfunction. Thus, the cGAS-STING pathway may be a potential target for the prevention of cardiovascular diseases in the elderly.

30-40% of people hospitalized with ACS are age 75 or older. ACS includes heart attack and unstable angina (heart-related chest pain). Cardiovascular changes that occur with normal aging make ACS more likely and may make diagnosing and treating it more complex: large arteries become stiffer; the heart muscle often works harder but pumps less effectively; blood vessels are less flexible and less able to respond to changes in the heart's oxygen needs; and there is an increased tendency to form blood clots. Sensory decline due to aging may also alter hearing, vision and pain sensations. Kidney function also declines with age, with more than one-third of people ages 65 and older having chronic kidney disease. These changes should be considered when diagnosing and treating ACS in older adults.

Clinical practice guidelines are based on clinical trial research. However, older adults are often excluded from clinical trials because their health care needs are more complex when compared to younger patients. ACS is more likely to occur without chest pain in older adults, presenting with symptoms such as shortness of breath, fainting or sudden confusion. Measuring levels of the enzyme troponin in the blood is a standard test to diagnose a heart attack in younger people. However, troponin levels may already be higher in older people. Age-related changes in metabolism, weight and muscle mass may necessitate different choices in anti-clotting medications to lower bleeding risk. As kidney function declines, the risk of kidney injury increases, particularly when contrast agents are used in imaging tests and procedures guided by imaging. Although many clinicians avoid cardiac rehabilitation for patients who are frail, they often benefit the most.

As people age, they are often diagnosed with health conditions that may be worsened by ACS or may complicate existing ACS. As these chronic conditions are treated, the number of medications prescribed may result in unwanted interactions or medications that treat one condition may worsen another. Older adults differ widely in their independence, physical or cognitive limitations, life expectancy, and goals for the future. The goals of care for older people with ACS should extend beyond clinical outcomes (such as bleeding, stroke, another heart attack or the need for repeat procedures to reopen arteries).

Adult stem cells are essential for tissue regeneration and homeostasis maintenance. Skeletal muscle possesses a remarkable regeneration capacity after acute injury because of its resident stem cells, muscle stem cells, or satellite cells (SCs). pon stimuli such as acute injury, quiescent SCs exit from quiescence to activate and re-enter the cell cycle for proliferation. They will further differentiate to repair the damaged tissue. Some activated SCs will return to quiescence through the self-renewal process to replenish the stem cell pool.

Eukaryotic DNA is highly organized into a nuclear structure called chromatin. The accessibility to the regulatory DNA elements restrains the gene expression, therefore defining the cell identity. In this study, we examined the chromatin accessibility changes of SCs, from quiescence exit, early activation, and regeneration, showing the trajectory of chromatin environment changes for SC activation in young and aged conditions. We showed that the chromatin environment of SCs is very compact during quiescence, becomes highly accessible on early activation, and gradually re-establish the compact state after long-term regeneration. We found that the old SCs exhibit a much more open chromatin environment, suggesting that the old SCs exhibit a chronically activated chromatin state.