An artery in the brain bursts. Blood rushes into the tissue, inducing free radicals that cause even more damage. The hemorrhage damages mitochondria, the site of energy production in cells. Astrocytes transfer their mitochondria to damaged neurons after a hemorrhage. These healthy mitochondria contain a "healing" peptide called humanin and an enzyme called manganese superoxide dismutase (Mn-SOD) that help neutralize free radicals.

Researchers injected mice with healthy mitochondria after a hemorrhage. The hemorrhage reduced levels of Mn-SOD in the mice brain and increased the number of free radicals. Using molecular tags, the researchers found that the rodents' neurons took up the mitochondria from the bloodstream. The mice who received the treatment showed improved neurological recovery, but the benefits decreased if the mice received mitochondria without the Mn-SOD enzyme. These results reveal mitochondria can transfer between brain cells to improve health and aide recovery.

Astrocytes release functional mitochondria (Mt) that play regulatory and pro-survival functions upon entering adjacent cells. We recently demonstrated that these released Mt could enter microglia to promote their reparative/pro-phagocytic phenotype that assists in hematoma cleanup and neurological recovery after intracerebral hemorrhage (ICH). However, a relevance of astrocytic Mt transfer into neurons in protecting brain after ICH is unclear. Here, we found that ICH causes a robust increase in superoxide generation and elevated oxidative damage that coincides with loss of the mitochondrial enzyme manganese superoxide dismutase (Mn-SOD). The damaging effect of ICH was reversed by intravenous transplantation of astrocytic Mt that upon entering the brain (and neurons), restored Mn-SOD levels and reduced neurological deficits in male mice subjected to ICH.

Using an in vitro ICH-like injury model in cultured neurons, we established that astrocytic Mt upon entering neurons prevented reactive oxygen species-induced oxidative stress and neuronal death by restoring neuronal Mn-SOD levels, while at the same time promoted neurite extension and upregulation of synaptogenesis-related gene expression. Furthermore, we found that Mt genome-encoded small peptide humanin (HN) that is normally abundant in Mt, could simulate Mt-transfer effect on neuronal Mn-SOD expression, oxidative stress, and neuroplasticity under ICH-like injury. This study demonstrates that adoptive astrocytic Mt transfer enhances neuronal Mn-SOD-mediated anti-oxidative defense and neuroplasticity in the brain, which potentiate functional recovery following ICH.

From a cellular and molecular perspective and from our own experience in a clinical trial setting, adipose-derived mesenchymal stem cells (AD-MSCs), bone marrow-derived MSCs (BM-MSCs) and umbilical cord derived MSCs (UC-MSCs) exhibit different functional activities and treatment effectiveness across a wide range of human diseases. In this paper, we have provided up-to-date data from the most recently published clinical trials conducted in neuronal diseases, endocrine and reproductive disorders, skin regeneration, pulmonary dysplasia, and cardiovascular diseases. The implications of the results and discussions presented in this review and in a very large body of comprehensive and excellent reviews as well as systematic analyses in the literature provide a different aspect and perspective on the use of MSCs from different sources in the treatment of human diseases.

We strongly believe that the field of regenerative medicine and MSC-based therapy will benefit from active discussion, which in turn will significantly advance our knowledge of MSCs. Based on the proposed mechanisms presented in this review, we suggest several key mechanistic issues and questions that need to be addressed in the future:

1. The confirmation and demonstration of the mechanism of action prove that tissue origin plays a significant role in the downstream applications of the originated MSCs.

2. Is it required that MSCs derived from particular cell sources need to have certain functionalities that are unique to or superior in the original tissue sources?

3. As mechanisms may rely on the secretion of factors from MSCs, it is important to identify the specific stimuli from the wound environments to understand how MSCs from different sources can exhibit similar functions in the same disease and whether or not MSCs derived from a particular source have stronger effects than their counterparts derived from other tissue sources.

4. Should we create "universal" MSCs that could be functionally equal in the treatment of all diseases regardless of their origin by modeling their genetic materials?

5. Can new sources of MSCs from either perinatal or adult tissues better stimulate the innate mechanisms of specific cell types in our body, providing a better tool for MSC-based treatment?

6. A potential 'priming' protocol that allows priming, activating, and switching the potency of MSCs from one source to another with a more appropriate clinical phenotype to treat certain diseases. This idea is potentially relevant to our suggestion that each MSC type could be more beneficial in downstream applications, and the development of such a "priming" protocol would allow us to expand the bioavailability of specific MSC types.

From our clinical perspective, the underlying proposal in our review is to no longer use MSCs for applications while disregarding their sources but rather to match the MSC tissue source to the application, shifting from one cell type for the treatment of all diseases to cell source-specific disease treatments. Whether the application of MSCs from different sources still shows their effectiveness to a certain extent in the treatment of diseases or not, the transplantation of MSCs derived from different sources for each particular disease needs to be further investigated, and protocols need to be established via multicentre, randomized, placebo-controlled phase II and III clinical trials.

The biology of aging is very complex, and the heterogeneity of aging is abundantly clear. Over a decade ago, nine hallmarks of aging were identified at the cellular and molecular level. The universality of the hallmarks of aging across species suggests their causal role in driving aging. However, establishing cause and consequence has proved challenging. Notably, more than one of the hallmarks reflect alterations to the nuclear genome, the integrity of which is vital to cell function. Here, we focus on the relationship of two hallmarks of aging affecting the nuclear genome: macromolecular damage and epigenetic alterations.

In eukaryotes, epigenetic modifications are critical because of their effects on gene transcriptional regulation. During development, different cell types establish and maintain specific epigenetic landscapes that dictate their cell fate. With aging, pronounced epigenetic alterations occur, including changes to DNA methylation and histone modifications, two key regulators of gene expression. Concurrent with these changes, spontaneous DNA lesions occur every single day within each of the 10^13 cells that constitute a human body. These lesions stall DNA and RNA polymerases, provoking a DNA damage response (DDR) that halts the cell cycle, enabling DNA repair.

Excessive or chronic DDR triggers irrevocable cell fate decisions, e.g., apoptosis and senescence. These two hallmarks of aging are intimately intertwined: DNA repair alters the epigenome and the epigenome impacts DNA repair efficiency. Furthermore, epigenetic marks to DNA can promote DNA damage. Genotoxic stress (DNA damage) is accepted as playing a causal role in cancer and in aging. Epigenome instability is established to play a causal role in cancer, but the mechanism by which epigenetic changes might play a causal role in aging are not well defined. Given the plethora of epigenetic clocks that correlate with chronological and even biological age, the causal relationship likely exists. Herein, we examine the current state of evidence that epigenetic alterations contribute to driving aging biology. In addition, because epigenetic changes impact genome stability, we explore the relationship between epigenetic marks and DNA damage.

Researchers boosted neurogenesis in Alzheimer's disease (AD) mice by genetically enhancing the survival of neuronal stem cells. The researchers deleted Bax, a gene that plays a major role in neuronal stem cell death, ultimately leading to the maturation of more new neurons. Increasing the production of new neurons in this way restored the animals' performance in two different tests measuring spatial recognition and contextual memory.

By fluorescently labeling neurons activated during memory acquisition and retrieval, the researchers determined that, in the brains of healthy mice, the neural circuits involved in storing memories include many newly formed neurons alongside older, more mature neurons. These memory-stowing circuits contain fewer new neurons in AD mice, but the integration of newly formed neurons was restored when neurogenesis was increased.

Further analyses of the neurons forming the memory-storing circuits revealed that boosting neurogenesis also increases the number of dendritic spines, which are structures in synapses known to be critical for memory formation, and restores a normal pattern of neuronal gene expression. Researchers confirmed the importance of newly formed neurons for memory formation by specifically inactivating them in the brains of AD mice. This reversed the benefits of boosting neurogenesis, preventing any improvement in the animals' memory.

Hippocampal neurogenesis is impaired in Alzheimer's disease (AD) patients and familial Alzheimer's disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.

Females and males often have markedly different mortality rates and life spans, but it is unclear why these forms of sexual dimorphism evolve. The unguarded X hypothesis contends that dimorphic life spans arise from sex differences in X or Z chromosome copy number (i.e., one copy in the "heterogametic" sex; two copies in the "homogametic" sex), which leads to a disproportionate expression of deleterious mutations by the heterogametic sex (e.g., mammalian males; avian females). Although data on adult sex ratios and sex-specific longevity are consistent with predictions of the unguarded X hypothesis, direct experimental evidence remains scant, and alternative explanations are difficult to rule out.

Using a simple population genetic model, we show that the unguarded X effect on sex differential mortality is a function of several reasonably well-studied evolutionary parameters, including the proportion of the genome that is sex linked, the genomic deleterious mutation rate, the mean dominance of deleterious mutations, the relative rates of mutation and strengths of selection in each sex, and the average effect of mutations on survival and longevity relative to their effects on fitness. We review published estimates of these parameters, parameterize our model with them, and show that unguarded X effects are too small to explain observed sex differences in life span across species. For example, sex differences in mean life span are known to often exceed 20% (e.g., in mammals), whereas our parameterized models predict unguarded X effects of a few percent (e.g., 1-3% in Drosophila and mammals). Indeed, these predicted unguarded X effects fall below statistical thresholds of detectability in most experiments, potentially explaining why direct tests of the hypothesis have generated little support for it.

Our results suggest that evolution of sexually dimorphic life spans is predominantly attributable to other mechanisms, potentially including "toxic Y" effects and sexual dimorphism for optimal investment in survival versus reproduction.

The breakdown of the blood-brain barrier accompanies many neurological conditions, including epilepsy and multiple sclerosis, and neurodegenerative diseases of aging, such as Alzheimer's disease and Parkinson's disease. "We are finding that the barrier is not just a protective check but also a source of regulation. It can cause problems rather than simply being a byproduct of neurodegeneration. We are learning now that there is definitely a two-way street."

The team used fruit fly larvae for their study. While fruit flies do not have the complexity of vertebrate blood-brain barriers, many of the properties are the same, in a system much easier to study. The key cells that provide a barrier for neurons in fruit flies are a specialized glia that function similarly to specialized endothelial cells that form the critical part of the blood brain barrier in higher vertebrates including humans.

The investigation began with a focus on enzymes called metalloproteinases because of their potential to be critical in interactions between glia and neurons. Using a genetic approach to look for what regulated expression of these enzymes, the team identified a pathway that is known as Notch signaling. Notch is found in both fruit flies and humans. It is associated with human diseases of the vasculature, dementia, and stroke. They discovered that Notch signaling in glia regulates the overall structure of the blood-brain barrier. When the signal is blocked, not only is barrier function impaired, but the fundamental work of the nervous system is affected, including neurotransmitter release and muscle contractions.

Under certain conditions, manipulation of Notch signaling affected how neurons fired, even though the blood-brain barrier remained intact. That indicated that there is signaling happening in the blood-brain barrier that is beyond just the maintenance of the barrier function. Breakdown in barrier function may be causing nervous system dysfunction, rather than being correlated with it or even a consequence of other damage.

Researchers had previously designed lipid nanoparticles (LNPs) that targeted gene editing packages to various organs. Targeting is achieved by modifying the chemical structure of the lipids that make up the bubbles, as well as other additives, until the researchers find a combination that prefers to go to the organ of interest. In this case, they found an LNP that concentrated in the lymph nodes after they were injected subcutaneously into mice. The researchers think the LNPs collect molecules from the blood stream on their surface, and those selected molecules bind to specific receptors in the target organ.

The lymphatic system, which includes the familiar lymph nodes that often swell up during an infection, is an important target for vaccines, because that's where immunity against a foreign antigen, or in this case, a cancer antigen, is acquired. If one thinks of the body as a field of battle - against viruses, bacteria, parasites, and tumors - and the B cells and T cells as soldiers, the lymph nodes are the boot camp where the B cells and T cells are trained to be more effective against the enemy. A key element of that training is the participation of dendritic cells and macrophages that introduce the antigens to the T and B cells and help fire them up.

The cancer vaccine works by delivering mRNA, allowing the cells to "read" the mRNA and produce viral antigens, small fragments of the virus that activate the immune system. With more vaccine going to the lymph nodes, researchers discovered that the cancer vaccine was absorbed by about a third of the dendritic cells and macrophages. That's significantly more than obtained with conventional vaccines. Mice with metastatic melanoma that were treated with the lymph-targeted vaccine showed significant inhibition of tumors and a 40% rate of complete response - no tumors - with no recurrence in the long-term when it was combined with another existing therapy that helps prevent cancer cells from suppressing an immune response. All the mice that were in complete remission prevented any new tumors from forming when injected later with metastatic tumor cells, showing that the cancer vaccine led to excellent immune memory.

Aging is now the most profound risk factor for almost all non-communicable diseases. Studies have shown that probiotics play a specific role in fighting aging. We used metagenomic sequencing to study the changes in gut microbes in different age groups and found that aging had the most significant effect on subjects' gut microbe structure. Our study divided the subjects (n = 614) into two groups by using 50 years as the age cut-off point for the grouping. Compared with the younger group, several species with altered abundance and specific functional pathways were found in the older group. At the species level, the abundance of Bacteroides fragilis, Bifidobacterium longum, Clostridium bolteae, Escherichia coli, Klebsiella pneumoniae, and Parabacteroides merdae were increased in older individuals. They were positively correlated to the pathways responsible for lipopolysaccharide (LPS) biosynthesis and the degradation of short-chain fatty acids (SCFAs). On the contrary, the levels of Barnesiella intestinihominis, Megamonas funiformis, and Subdoligranulum unclassified were decreased in the older group, which negatively correlated with the above pathways.

Functional prediction revealed 92 metabolic pathways enriched in the older group significantly higher than those in the younger group, especially pathways related to LPS biosynthesis and the degradation of SCFAs. Additionally, we established a simple non-invasive model of aging, nine species (Bacteroides fragilis, Barnesiella intestinihominis, Bifidobacterium longum, Clostridium bolteae, Escherichia coli, Klebsiella pneumoniae, Megamonas funiformis, Parabacteroides merdae, and Subdoligranulum unclassified) were selected to construct the model. The model implied that supplemented probiotics might influence aging. We discuss the features of the aging microbiota that make it more amenable to pre-and probiotic interventions. We speculate these metabolic pathways of gut microbiota can be associated with the immune status and inflammation of older adults. Health interventions that promote a diverse microbiome could influence the health of older adults.

"As you age, you have an increase in the number of senescent cardiac stem progenitor cells, and these have a reduced potential to proliferate and a reduced potential to differentiate. So, they're no longer able to do what we need them to do. One approach to solving the issues caused by senescent cells is the use of drugs called senolytics that target and kill them. We've used the drugs dasatinib and quercetin to eliminate senescent cells, and we've shown that when you eliminate senescent cells in an aged mouse model, you see a rejuvenation of the heart's regenerative potential. You have activation of the cardiac stem progenitor cells, cardiomyocyte proliferation, and decreased cardiac hypertrophy and fibrosis."

"We have devised these human cell co-culture in vitro systems, where we can test the effects of senescence and also the effects of senolytics on human cells. We've shown that senescent cells can impair survival and proliferation of a variety of cell types found in the heart. When we treat the co-cultures with senolytics to remove the senescent cells, we see an improvement in cell survival, proliferation, and improved angiogenesis. And we do these experiments in a human model, which is so important for us, to show translation."

Inflammation is a defining factor in disease progression; epigenetic modifications of this first line of defence pathway can affect many physiological and pathological conditions, like aging and tumorigenesis. Inflammageing, one of the hallmarks of aging, represents a chronic, low key but a persistent inflammatory state. Oxidative stress, alterations in mitochondrial DNA (mtDNA) copy number and mis-localized extra-mitochondrial mtDNA are suggested to directly induce various immune response pathways. This could ultimately perturb cellular homeostasis and lead to pathological consequences.

Epigenetic remodelling of mtDNA by DNA methylation, post-translational modifications of mtDNA binding proteins and regulation of mitochondrial gene expression by nuclear DNA or mtDNA encoded non-coding RNAs, are suggested to directly correlate with the onset and progression of various types of cancer. Mitochondria are also capable of regulating immune response to various infections and tissue damage by producing pro- or anti-inflammatory signals. This occurs by altering the levels of mitochondrial metabolites and reactive oxygen species (ROS) levels.

Since mitochondria are known as the guardians of the inflammatory response, it is plausible that mitochondrial epigenetics might play a pivotal role in inflammation. Thus, strategies aimed at compensating for changes brought about by mitochondrial epigenetics like restoration of dysfunctional mtDNA or TFAM activity might emerge as promising preventive and therapeutic interventions for pathological conditions occurring due to exacerbated inflammation.

Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.

No one knows entirely why epigenetic clocks work. Some but not all of the genes and molecular pathways involved have been identified, and researchers are still learning how DNA methylation patterns affect the behaviors and health of cells, tissues and organs. Researchers have begun seeking biological correlates for epigenetic aging. Perturbations of the biochemical pathways the body uses to sense its need for nutrients slow aging, they recently discovered, in accordance with the effects of calorie-restricted diets on aging. Derailing the workings of mitochondria speeds it up. The clock also tracks the maturation of stem cells. If these processes are connected at a deeper level, epigenetic clocks may reveal unifying mechanisms for aging, researchers wrote in a 2022 paper.

What those unifying mechanisms might be or why methylation status tracks aging so well, however, is yet to be fully determined. "We don't really know if epigenetic clocks are causally linked with aging." Even if they are, epigenetic clocks are almost certainly measuring only part of what occurs during aging. "Whether they are actually measuring more than a single dimension of biological age is not clear. This is part of the problem here - the conflation of epigenetic age with biological age. Those are not equivalent in my view."

Researchers speculate that the methylation changes reflect a loss of cellular identity with age. All cells in the body have the same DNA, so what makes a liver cell a liver cell and a heart cell a heart cell is the pattern of gene expression, which epigenetics controls. As changes in methylation accumulate with age, some of those controls might be lost, replaced by re-emerging developmental programs that should be switched off. Nonetheless, methylation clocks have limited clinical uses at present. People can buy a readout of their biological age from various commercial sources, but not only are the results often inconsistent, they lack clinical relevance because the clocks were meant for group-level analyses in research. They are not built to be predictive at an individual level.

Comprehending the role of molecular processes such as DNA damage repair, telomere shortening, nuclear and chromatin changes along with epigenetic alterations which drive aging as well as aging related diseases may hold a key to the "elixir of life." Of late the resurrection of aged cells back to cellular proliferation has garnered attention from various molecular biologists. The use of Yamanaka factors reprograms cells to a partially undifferentiated stage which is shown to ameliorate some of the functions of aged fibroblasts. The transient expression of these factors rescued the levels of H3K9me3 and DNA damage marks such as γ-H2AX. These studies fortify the beneficial role of heterochromatin in protecting the genome from DNA damage and neoplastic transformation.

However, there remain several uncharted domains: Is heterochromatin alone sufficient to extend lifespan? Is the reorganization of the heterochromatin guided by the changed DNA methylome in aged cells? A varied number of histone variants are expressed inside as well as outside of the senescence associated heterochromatin foci (SAHF). What directs them to their specific genomic location upon senescence? The complexity and confusion arise as cells induced by different stress mediated pathways show different epigenetic signatures or varied chromatin organization. Senescent cells found in the pre-cancerous lesions exhibit increased levels of heterochromatic histone modifications (H3K9me2/3 and HP1γ) but lack in SAHF. This discrepancy might be due to the variation in the extent of heterochromatinization of the genome.

We posit that analyzing the biophysical and mechanical nature of aged chromatin polymer in different cell types might provide clues to its natural decay and dysfunction. Despite current technological challenges, even elucidating the half-life or turnover of chromatin factors, including post-translational modifications of nucleosomes, repair factors, chromatin remodelers could be an important start. Knowing these parameters, we can better understand and potentially model how the nuclear landscape changes as cells age.

The study of aging has long been linked with the study of metabolism, as early theories pointed to the rate of metabolism and by-products of metabolism as drivers of aging processes. The earliest recognized interventions that caused life span extension in model organisms targeted nutritional and metabolic pathways. A more nuanced view of aging mechanisms has since emerged that identifies dysregulated metabolism as one of many hallmarks of aging.

Epidemiologic studies of the oldest old humans, centenarians, strive to identify unifying lifestyle elements, nutritional patterns, and genetic or metabolomic signatures that clearly underlie longevity. Certainly, the female sex confers a longevity advantage, as centenarians are disproportionately female. This pattern of increased female longevity is seen across species; however, its underpinnings are incompletely understood. Social engagement, diet composition, and fasting patterns have been identified as factors that may confer longevity on a population level. Indeed, caloric restriction is known to promote longevity and delay the onset of age-related disease in multiple species. The people of Okinawa, who before the influence of a Western diet ate only 83% of the average calories consumed by the mainland Japanese population, were observed to have a longer life span and lower mortality from coronary artery disease and cancer than mainland Japanese or American people.

Long-lived humans may have some advantage in glucose handling. In one study, human centenarians (older than 100 years of age) had better insulin sensitivity than did younger controls older than 75 years of age. Insulin sensitivity is associated with healthy aging across species, and in fact modifications in glucose signaling pathways were some of the first interventions to lead to life span extension in model systems including yeast and Caenorhabditis elegans. Similarly, inhibition of the growth hormone (GH) axis is associated with longevity in model systems. However, lifelong GH deficiency is also accompanied by smaller body size, which in humans may confer undesirable effects such as adipose tissue accumulation and intellectual deficiency. Body size is typically inversely correlated with longevity (such as in dogs), but this does not seem to be the case in humans.