A recent study demonstrated that a methionine-restricted (MR) diet improved mitochondrial function and upregulated autophagy-related genes, resulting in a 45% extension of rodent lifespan. Other studies also demonstrated that MR regulates energy expenditure in the aged musculoskeletal system, activated insulin signaling that improved type II diabetes, and decreased lipid peroxidation that reduced hyperlipidemia. Clearly, decreasing dietary methionine has beneficial physiologic effects. However, a pathway connecting methionine to these pathologies is yet to be elucidated. Methionine breakdown begins with MAT2A, which catalyzes the production of S-adenosyl methionine (SAMe) from methionine.

Previously, our laboratory reported similar pathologies affecting cells from progeria patients and cells undergone replicative senescence. Further, we demonstrated that with ectopic expression of the pluripotency factor, NANOG could effectively reverse aging hallmarks and reestablish young attributes in older cells to restore their myogenic differentiation capacity, decrease senescence-associated beta-galactosidase (SA-βgal), restore mitochondrial function, and repair DNA damage. NANOG also restored the ability of senescent myoblasts to differentiate into healthy skeletal myotubes and ameliorated the hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction in human skeletal myoblasts and restored the number of myogenic progenitors in a mouse model of premature aging.

However, the mechanism through which NANOG imparts its rejuvenating effects is not known. Using NANOG as an investigative tool, we examined whether metabolic impairments due to senescence or premature aging could be reversed, restoring muscle function. We discovered that senescent myoblasts used methionine to meet their metabolic demands and that increased use of methionine contributed to the loss of skeletal muscle function. Conversely, inhibition of MAT2A catabolism by NANOG expression or chemical inhibition restored glucose-based bioenergetics and the force-generating capacity of aged skeletal muscle in a mouse model of premature aging.

Idiopathic pulmonary fibrosis (IPF) is a commonly diagnosed chronic, progressive, and fibrotic interstitial pneumonia that accounts for 20-30% of interstitial lung diseases. It usually occurs in middle-aged and elderly individuals. It is now generally accepted that persistent alveolar epithelial damage and repair dysregulation are the principal mechanisms leading to progressive pulmonary fibrosis.

Repetitive epithelial cell injury and deficiencies in regeneration result in the release of mediators, including cytokines, chemokines, fibrogenic factors, coagulant proteins, oxidants, and regulators of apoptosis. This leads to the recruitment, proliferation, and activation of interstitial fibroblasts to form fibrotic foci. Additionally, excessive deposition of the extracellular matrix leads to destruction of lung parenchymal structures. Interestingly, a variety of cells, including alveolar epithelial type II cells (ATII) and fibroblasts, can drive IPF. Regardless of the driver cell types, senescence leads to a decrease in the repair capacity of damaged alveolar epithelium. As a result, fibrous tissue replaces the damaged alveolar epithelium.

From a histopathological point of view, IPF formation is a dynamic process involving complex interactions among epithelial cells, fibroblasts, immune cells (such as macrophages and T lymphocytes), and endothelial cells. Alveolar epithelial cells undergo cytoskeletal remodeling and acquire a mesenchymal phenotype through epithelial-mesenchymal transition (EMT), in which epithelial cells lose intercellular attachment, polarity, and epithelial-specific markers, leading to fibrosis.

Some investigators have identified ATII as a major player in the synthesis of transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) in lung biopsies from patients with IPF. In the process of organ fibrosis formation, including pulmonary fibrosis, TGF-β acts as the master switch for the induction of the EMT process. In particular, TGF-β mediates fibrous proliferative effects by inducing apoptosis in alveolar epithelial type I (ATI) cells. However, there is no direct evidence that TGF-β promotes IPF by inducing senescence in the alveolar epithelial cells.

In the lungs of patients with IPF, the ability of ATII cells to transdifferentiate into ATI cells is diminished. Emerging evidence also suggests that triggering ATII senescence can promote IPF. Therefore, studying the mechanisms of cellular senescence in the lung microenvironment is crucial to understand IPF pathogenesis and progression. Decreasing senescent alveolar epithelial cells may be a promising strategy for the treatment of IPF. Therefore, further investigations into new treatments of IPF by applying inhibitors of relevant signaling pathways, as well as senolytic drugs, are warranted.

The thymus is a specified immune organ that provides an inductive environment for the generation of T cells that play a critical role in the adaptive immune system. Although the thymus continues to export T cells throughout life, it undergoes a profound atrophy with age, a process termed thymic involution, resulting in decreased numbers and functional capacity of T cells in the older adult, which has direct etiological linkages with many diseases. Furthermore, T cell immune deficiency in the older adult is exacerbated when the immune system is insulted by chemotherapy, radiotherapy, infections (e.g. HIV), and preparative regimens for foreign tissue or organ transplants. Therefore, restoring thymus function in the older adult has important implications.

We have previously reported that intrathymic injection (i.t.) of a recombinant (r) protein containing FOXN1 and a protein transduction domain embedded in the HIV transactivator of transcription (TAT) protein increases the number of thymic epithelial cells (TECs) in mice that have undergone hematopoietic stem cell transplantation. Consequently, these mice had enhanced thymopoiesis, an improved thymic output and an increased number of naïve T cells in the periphery. However, i.t. injection may not be an ideal choice for clinical applications.

It has been reported that chemokine CCL25 is highly expressed in thymic tissue, especially thymic stroma. CCR9 is the receptor for CCL25. Unlike other CC chemokine receptors, CCR9 shows a strict specificity for its ligand CCL25. It has been shown intramural injection of a fusion protein containing the N-terminal of CCR9 and IL-7 increased the content of IL-7 in the thymus as compared to injection of IL-7 alone.

In this study, we develop a rFOXN1 fusion protein that contains the N-terminal of CCR9, FOXN1, and TAT. We show here that, when injected intravenously (i.v.) into aged mice, the rFOXN1 fusion protein can migrate into the thymus and enhance T cell generation in the thymus, resulting in increased number of peripheral T cells. Our results suggest that the rFOXN1 fusion protein has the potential to be used in preventing and treating T cell immunodeficiency in the older adult.

The hippocampus is a brain region closely related to spatial learning and memory. Adult neural stem cells (NSCs), which are located in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, play important roles in the function of the hippocampus. NSCs have the ability to proliferate, either generating two NSCs to maintain NSC pools through symmetric division or generating one NSC and one neural progenitor cell (NPC) through asymmetric division. NPCs then further differentiate into particular cell types, such as neurons or astrocytes. Studies on rodents have shown that proliferation and neurogenesis of NSCs persist throughout the lifespan; however, adult neurogenesis decreases with age, and this decrease is involved in cognitive and memory declines, indicating that abnormalities in hippocampal NSCs are one of the main causes of age-related deterioration in hippocampus-dependent cognition.

Proliferation and neurogenesis of NSCs are exquisitely regulated by extrinsic and intrinsic factors, including secreted molecules, neurotransmitters, transcription factors, and epigenetic regulators. Among these, miRNAs, which are enriched in the brain, have been shown to be widely involved in the regulation of NSC proliferation and differentiation. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes.

The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allows for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes.

By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclasts and marrow adipocytes. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide the first proof-of-concept evidence that local senolysis has health benefits in the context of aging, but importantly, local senolysis only partially replicates the benefits of systemic senolysis. Further, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.

The transplantation of pluripotent stem cell-derived neural precursors into the cortex is an exciting potential approach to repair the brain. To achieve this goal, grafted cells must re-establish damaged neural circuits that participate in the restoration of lost behavioral function. Significant progress has been made in demonstrating the feasibility of transplanting precursor cells to replace neurons in the cortex. Graft-derived neurons can survive for years in mice and differentiate into appropriate neuronal subtypes that exhibit normal electrophysiological activity, project long distances outside of the graft to appropriate targets, synaptically integrate with surrounding host neurons, and respond to sensory input and participate in motor output.

Despite these significant discoveries, it is unclear whether grafted neurons in the neocortex can encode useful behavior as a result of their electrophysiological activity. Reported behavioral benefits are instead a result of activity-independent functions such as the secretion of anti-inflammatory or neurotrophic factors. The inability to demonstrate that electrophysiological activity of grafted neurons encode useful behavior is not surprising considering there are cortical cell types that are thus far missing in grafts, in addition to these grafts lacking normal cortical cytoarchitecture. While cerebral organoids display a subset of similar characteristics to a normal fetal cortex, their differentiation has thus far been abnormal after transplantation. Therefore, there is currently no method of generating facsimiles of neocortical tissue in adults, whether for the purpose of study or therapy.

The goal of this study is to provide an initial proof of concept for a neocortical grafting platform that supports (1) the survival and differentiation of the major neocortical cell types, (2) vascularization, (3) neuronal integration, and (4) layering. Toward this goal, we tested whether grafting cells in a three-dimensional scaffold could sustain the differentiation of all the major cortical cell types, vascularization, and a layered cytoarchitecture. Using dissociated mouse cortical fetal cells mixed with a commercial scaffold, we found that the neuronal, glial, and vascular components within the graft survived and successfully integrated with the host tissue. Our results suggest that this platform is suitable for future optimization and testing of structured, vascularized, multi-cell type neocortical tissue prototypes.

In this study, we asked the question whether the cellular senescence-lowering effect of exercise in human skeletal muscle can occur only at the intensity sufficient to induce DNA damage and inflammation. Biopsied vastus lateralis of 9 sedentary men (age 26.1 ± 2.5 y) were assessed before and after a single bout of moderate steady state exercise (SSE, 60% maximal aerobic power) and high intensity interval exercise (HIIE, 120% maximal aerobic power). Increases in cell infiltration (+1.2 folds), DNA strand break (+1.3 folds), and γ-H2AX+ myofibers (+1.1 folds) occurred immediately after HIIE and returned to baseline in 24 hours. Muscle p16Ink4a mRNA decreased 24 hours after HIIE. SSE had no effect on cell infiltration, p16Ink4a mRNA, and DNA strand break in muscle tissues.

The major findings are as follows: (1) Cellular senescence-lowering effect of aerobic exercise can occur only at high intensity. SSE with similar exercise work failed to lower the p16INK4a mRNA in human skeletal muscle within the 24-h recovery period; (2) HIIE triggered immediate increases in cell infiltration and γ-H2AX+ myofibers, followed by a decreased p16INK4a mRNA in human skeletal muscle 24 hours after recovery; (3) By further examining the individual responses, the senolytic effect of HIIE were contributed solely from those participants with high pre-exercise p16INK4a mRNA in skeletal muscles.

High intensity exercise is known to cause greater levels of lactate production and acidosis than low intensity exercise. Decreased pH has been reported to be a danger signal to activate innate immune response and immune cells are functioned to recognize and clear senescent cells by phagocytosis in humans. Therefore, the acute changes in the microenvironment during and after exercise may be a selection pressure to aged stem cell population resided in the skeletal muscle. Exercise intensity determines the magnitude of cell renewal during a brief period of inflammation.

Taken together, decreased cellular senescence 24 hours after HIIE is best explained by senescent cell clearance following a brief increase of bone marrow cell infiltration into challenged skeletal muscle to participate in the early phagocytic and late regenerative phases of inflammation. DNA damage is a potent stimulator of inflammation. In this study, a fast resolution of DNA damage/repair response 24 hours following HIIE suggests an efficient clearance of senescent cells with DNA damage in human skeletal muscle to resolve the inflammation.

Unlike humans and other mammals, which become less fertile with age, naked mole-rats can reproduce throughout their remarkably long lifespans. For most mammals, including humans and mice, females are born with a finite number of egg cells, which are produced in utero via a process called oogenesis. Because this limited supply of egg cells depletes over time - some are released during ovulation, but most simply die - fertility declines with age. In contrast, naked mole-rat queens can breed right through old age, suggesting the rodents have special processes to preserve their ovarian reserve and avoid waning fertility. "There are three possibilities for how they do this: They are born with a lot of egg cells, not as many of these cells die, or they continue to create more egg cells after birth. My favorite hypothesis is that they use a cocktail of all three." Sure enough, researchers found evidence for each of the three processes.

The researchers compared ovaries from naked mole-rats and mice across different stages of development. Despite their similar sizes, mice live four years at most and start to show a drop in fertility by nine months, whereas naked mole-rats have a life expectancy of 30 years or more. They found that naked mole-rat females have exceptionally large numbers of egg cells compared to mice and that death rates of these cells were lower than in mice. For example, at 8 days old, a naked mole-rat female has on average 1.5 million egg cells, about 95 times more than mice of the same age. Most remarkably, the study found that oogenesis happens postnatally in naked mole-rats. Egg precursor cells were actively dividing in 3-month-old animals, and these precursors were found in 10-year-old animals, suggesting that oogenesis could continue throughout their lives.

Lack of exercise is a health concern worldwide. According to WHO, 31% of the world's population does not attain the minimum required level of physical activity. This unhealthy lifestyle is the fourth leading cause of death worldwide with approximately 3.2 million deaths annually. This situation is continuously worsening and poses a substantial burden on health systems and societies. A considerable portion of health conditions can be attributed to physical inactivity. Sedentary behavior and physical inactivity are the leading risk factors for cardiovascular disease and all-cause mortality. Compared with people who have previously been physically active, those who are inactive have a higher risk of developing neurological diseases.

Recognizing that many chronic diseases are closely related to poor lifestyle habits and that exercise plays a role in a variety of health conditions, the American College of Sports Medicine and the American Medical Association suggested that "exercise is medicine". Subsequently, a multinational collaboration on "exercise is medicine" began and this initiative was centered on global awareness. In this initiative, it was suggested that patients' level of physical activity be added to their medical records, and behavioral physical activity counseling should be provided through a clinical decision support system.

Specifically, the exercise situation of each patient should be considered as a vital sign in each visit, then healthcare workers should provide professional physical activity guidance for patients' exercise situation and health needs. This initiative emphasized that exercise should be used as medical advice in clinical settings. Hence it is not just improving patients' exercise awareness that is significant, but more so the formation of normative medical work for exercise guidance and the healthcare workers' awareness of exercise effects in health.

Using data from the population-based 1946 British birth cohort, which has followed people born in the same week of 1946, previous studies have demonstrated beneficial effects of midlife physical activity on midlife verbal memory and search speed decline. Here, we extend this work by taking a life course approach to evaluate the effects of physical activity timing, frequency and maintenance, spanning over 30 years, with later-life cognitive function. We assess three measures of later-life cognitive function including a measure of cognitive state, verbal memory, and processing speed. We further aim to investigate to what extent, these effects are explained by pathways including earlier-life influences, cardiovascular health, and mental health.

To investigate the effect of timing of physical activity, we investigated the strength of associations between a range of cognitive tests at age 69 with participation in physical activity at the ages of 36, 43, 53, 60 and 69. We then investigated whether any associations observed are best explained by physical activity in specific 'sensitive' periods across the life course, or being physically active across multiple time periods.

Being physically active, at all assessments in adulthood, was associated with higher cognition at age 69. For cognitive state and verbal memory, the effect sizes were similar across all adult ages, and between those who were moderately and most physically active. The strongest association was between sustained cumulative physical activity and later-life cognitive state, in a dose-response manner. Thus being physically active at any time in adulthood, and to any extent, is linked with higher later-life cognitive state, but lifelong maintenance of physical activity was most optimal.

Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD+ levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters.

A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.

New findings, based on an analysis of data from the Centers for Disease Control and Prevention (CDC) from 1999-2020, indicate that age-adjusted rates of death attributed to acute myocardial infarction (the medical term for heart attack) fell by an average of over 4% per year across all racial groups over the two-decade period. "Researchers often highlight the bad news, but people should know that even if we're not there yet, we're making progress in the right direction. I think the reasons are multifactorial, spanning all the way from health-promoting and prevention activities through treatment during and after a heart attack."

Researchers found the overall rate of death from heart attack, adjusted for age, fell from about 87 deaths per 100,000 people in 1999 to about 38 deaths per 100,000 people in 2020. It is difficult to definitively determine whether the decline is the result of fewer heart attacks occurring or better rates of survival when they do occur because of new diagnostic strategies and treatment options, researchers said. For example, hospitals now frequently test for troponin in the blood when a heart attack is suspected, which can help clinicians diagnose a heart attack at an earlier stage than was possible with previous diagnostic strategies. This change has led to earlier and more sensitive heart attack detection but also makes it challenging to compare data on heart attacks over time.

On the prevention side, the public has become more aware of the need to reduce cardiovascular risk factors through steps such as quitting smoking and managing cholesterol. Clinicians also have a better understanding of the signs of a heart attack and improved tools to quickly diagnose and treat them when they occur. More hospitals are also equipped with mechanical support devices to assist with heart attack treatment and new medications such as potent antiplatelet drugs have become available, which may have improved survival rates and reduced the likelihood of a second heart attack.

Bioprinting is based on 3D-printing technology, using cells and biopolymer to create biological structures and tissues. One of the most promising types of 3D-bioprinting is called digital light processing (DLP) bioprinting. Within this branch of 3D-bioprinting, progress has been impeded by practical and technical impediments. It has proven difficult to print tissues with high cell densities and finely resolved structures.

DLP-based 3D bioprinting uses a digital micromirror device (DMD) to project a 2D cross-section of the 3D model to the photo-crosslinkable bioink. When exposed to light, the photocrosslinkable bioink, which can be either synthetic or natural, solidifies. Then, a motorized stage lifts up the bioink by a few tens microns to 200 microns, which allows uncured bioink to refill the gap. When the next cross-section is projected to the bioink, a new layer solidifies and the process repeats.

When all goes well, a newly formed layer precisely matches the shape of the projected cross-section. However, with existing methods, the incorporation of cells in the bioink can cause severe light scattering, which blurs the projected light in the bioink. As a result, the newly formed layers cannot replicate the fine details of the projected cross-sections. The researchers reduced this light-scattering effect by tenfold, allowing them to print with high cell densities and high resolution thanks to the contrast agent iodixanol, a new ingredient in the bioink.

Tuning the refractive index of the bioink minimizes the scattering effect and significantly improves the fabrication. The new research shows that a ~50 µm feature size can be achieved in a refractive-index-matched gelatin methacrylate (GelMA) bioink with a cell density as high as 0.1 billion/mL. This approach introduces a few novel technical innovations, including a hollow organic vascular network embedded in a cell-laden thick tissue, enabling it for perfused and long-term culture, and a snow-flake and spoke shape to showcase the high resolution for both positive and negative features.

Proteostasis is the sum of reactions and signalling pathways related to the synthesis, folding, trafficking, disaggregation, and degradation of proteins. One of the hallmarks of aging is a decline in proteostasis. Unsurprisingly, defects in all major steps of proteostasis are related to the accumulation of toxic aggregates and misfolded proteins, a key feature of neurodegenerative diseases. Throughout evolution, a range of protein quality-control mechanisms have emerged, some of which are specialised in monitoring the proteome within specific subcellular compartments. Examples are the cytosolic heat-shock response (HSR), the mitochondrial unfolded protein response (UPRmt), and the unfolded protein response of the endoplasmic reticulum (UPRER). The mechanisms underlying age-related proteostasis collapse are still not completely understood, but studies using Caenorhabditis elegans and mice suggest that it initiates during early adulthood preceding the emergence of age-related diseases.

A fundamental question in biogerontology is why animals lose the ability to maintain proteostasis with aging. A new study observed that an age-related increase in ribosome pausing occurs driven by a reduced activity of the ribosome quality control (RQC) pathway. Another provocative study, in mice, argued that error-prone translation caused by ribosomal ambiguity mutations induces phenotypes that more closely match the progression of Alzheimer's disease than amyloid-β overexpression models do. Their findings suggest that the accumulation of random mutations in DNA over time may induce increased protein misfolding, sequestering away key components of the proteostasis maintenance machinery, such as chaperones, ultimately causing a collapse in proteostasis.

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction that occurs during aging. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect more than 89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function.

G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue and mutation type dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with Elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age suggests a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.