November saw leading lights from across the longevity sector come together in London to announce the formation of the Longevity Biotechnology Association (LBA). The non-profit organisation says it aims to represent those behind the development of "new medicines and therapies to prevent and cure, rather than merely manage, the health conditions of late life."

Kicking off in June, the On Deck Longevity Biotech Fellowship is on a mission to increase the number of people working to build longevity biotechnology companies. Nathan Cheng, ODLB's Program Director hopes the Fellowship will address the fact that as more and more capital flows into the antiaging biotechnology sector, the major obstacle to progress has become the lack of founders.

The National Institute on Aging, which is part of the National Institutes of Health, invited applications for longevity clinical trials to slow aging and prevent or treat age-related diseases in February of this year. Previously, the FDA has approved biotech interventions that address individual diseases, rather than tackling aging itself. However, this funding opportunity is available to researchers who want to treat multiple chronic conditions by modulating fundamental aging-related mechanisms. In short, those who want to target aging itself.

The worlds of cryptocurrency, blockchain, and longevity have collided this year in several very interesting ways. VitaDAO's crypto auction raised 400% of expectation, gathering in over 5 million for longevity research, and the Longevity Science Foundation began to use blockchain technology in its funding selection process. 2021 also saw cryptocurrency HEX founder Richard Heart's creation of a new currency, Pulse. Prior to the launch of this new cryptocurrency, Heart made headlines with an airdrop, in which he gave away some Pulse to those who donated to the SENS Research Foundation (SRF) during a specific 'sacrifice' window.

Seeking to cut the Gordianesque knot of red tape, the Longevity Impetus Grants launched this year, with the aim of speeding up research that slows down aging. Seeking to have a broad impact on the longevity field, the grants will support projects that challenge assumptions, develop new tools and methodologies, discover new ways to reverse aging processes, and/or synthesise isolated manifestations of aging into a systemic perspective. With 26 million to give away (including 1500 Ethereum from Vitalik Buterin), grants will be 10k-500k, with decisions made in three weeks.

Recent events have, of course, thrown a spotlight on our immune systems, but several stories this year have focused on our immune systems for other reasons. In May, we reported how scientists are leveraging the power of immune cells to clear the body of senescent cells that contribute to aging and many chronic diseases in the hope that this new understanding may open the door to new ways of treating age-related chronic diseases with immunotherapy. Senotherapeutic therapies are one way to remove senescent cells, but if our body's own natural surveillance system could be stimulated to do the job, it could be a way to tackle senescence without side effects.

In July, the Buck Institute for Research on Aging announced an aging clock for immunosenescence. An inflammatory clock of aging (iAge) - it measures inflammatory load, rather than causing controversy - predicts multi-morbidity, frailty, immune health, cardiovascular aging and is also associated with exceptional longevity in centenarians.

With much of the world focused on the potential of young blood to improve longevity, our interview with UC Berkeley professor Irina Conboy challenged that view. She's well-qualified to do so, having worked in the lab that produced the seminal 2005 paper on heterochronic parabiosis reversing aging in mice. "We think that if you inject an old person with bodily fluids from a young person, nothing good will happen, unless there is a critical blood loss and a need for a transfusion. But if you can neutralise or remove some determinant proteins that are elevated in ways that become counterproductive, then that old person will become younger."

Targeting senescent cells (old cells that don't die off and build up in our bodies as we age) continued to be a hot topic in longevity this year - so much so, we even wrote a dedicated market report on it! But, with several companies now actively developing senolytic therapeutics that target and kill senescent cells, we spoke to Buck Institute professor Judith Campisi, one of the world's leading authorities on senescence, to get her perspective. "The first question we want to know is, are these different cell populations good or bad, or both? We just don't know. We definitely want senolytics that hit the bad guys, and not the good guys - and we don't have that yet. We don't have that at all."

When it comes to the study of aging, the Buck Institute in California is synonymous with some of the most cutting edge research in the field. This year, the Buck also came to our attention on the commercial side of longevity, with three of its top researchers joining forces to start a company called Gerostate Alpha. Our two-part interview covered the formation of the company, and its goal to discover "interventions that attenuate or halt multiple aging indications simultaneously." Gerostate sets itself apart from many other companies in the field by not focusing on a particular pathway, and concentrating instead on compounds that extend lifespan in mice.

A lot of companies we spoke to over the past 12 months were particularly interested in mitochondria's role in longevity. These miniature organs within our cells play a key role in providing the energy needed for growth, repair, and rejuvenation, and their decline as we age is linked to a range of age-related diseases. US biotech Cohbar has been working in this field longer than most, and our interview with the company's CEO shed some light on the progress made to date, including the discovery of key peptides.

The mechanisms of increased stiffness in aging are both extracellular and cellular. The three main aortic wall components, elastin, collagen, and smooth muscle cells, vary along the length of the aortic tree. With aging, these components of the aortic wall are altered. The number of elastic fibers and smooth muscle cells in the tunica media decrease, while collagen fibers increase with advancing age. The number of smooth muscle cells in the tunica media decreases with age and vascular smooth muscle cell migration from the tunica media thickens the intima.

The most important mechanism studied as a cause of age-related increases in vascular stiffness is alteration in the extracellular matrix (ECM), resulting from an increase in collagen and decrease in elastin. The ECM is composed of a complex network of different matrix proteins, metalloproteases, and glycosaminoglycans, which are also responsible for the structural integrity of the vasculature, and therefore contribute to its stiffness. Collagen is a very stiff protein with the function of limiting vessel elasticity and distension, and is therefore fundamental to defining the stiffness of the arterial wall. Collagen deposition throughout the vasculature increases with age, which alters the normal ECM network. This has been shown to occur in the intima, media, and adventitia of the vessel wall leading to substantial changes in its morphology and function. In addition to increased collagen deposition, there is also increased non-enzymatic glycation. This is also responsible for age-related increases in arterial stiffness, as it induces collagen cross-linking, which increases stiffness.

Unlike collagen, elastin, the other major ECM protein, provides flexibility and extensibility of the vessel wall. Elastin fibers are mainly found in the medial layer of large elastic arteries and are oriented around smooth muscle cells and collagen. Degradation of elastin fibers with aging is mediated by the increases of proteolytic enzymes, e.g., matrix metalloproteases (MMP), which degrade elastin fibers, resulting in an increase in collagen/elastin ratio, which in turn increase vessel wall stiffness. Nevertheless, the extent to which increases in collagen and decreases in elastin contribute to increased vascular stiffness with aging remains controversial.

Calcification of the vessel wall occurs with normal aging, reducing the vessel wall's distensibility. In humans there is a direct correlation between aortic calcification and arterial stiffness. Calcinosis of arterial walls with aging has been associated with increased cholesterol content in the elderly, suggesting a relationship between these processes. However, it is unknown which process occurs first, although some have speculated that calcinosis increases interaction with cholesterol molecules in the arterial wall. Increases in oxidative stress that occur with aging, mainly due to decreases in mitophagy and autophagy, stimulate vascular calcification by activating several signaling cascades. One of the best studied signaling pathways involves the upregulation of bone morphogenetic proteins due to increases in oxidative stress, which results in increased vascular calcification.

The vascular endothelium is the innermost, monolayer of cells in blood vessels. When the endothelium is healthy, vascular tone is regulated by a balance of vasoconstriction and vasodilation; the latter controlled by nitric oxide (NO) release. Reduced bioavailability of nitric oxide leads to endothelial dysfunction, resulting in impaired vasodilation, which increases arterial stiffness. Endothelium impairment and decreased NO bioavailability occur with normal aging, ultimately leading to a proinflammatory, vasoconstrictive state, resulting in increased vascular fibrosis and arterial stiffness. Furthermore, endothelial dysfunction leads to an increase in oxidative stress through an increase in the production of superoxide causing damage to the vessels leading to changes in hemodynamics. Recently, it has also been proposed that autophagy, the cellular housekeeping mechanism that maintains cellular homeostasis, decreases in the aging endothelium, further leading to increases in oxidative stress. This was further confirmed with the use of a pro-autophagy treatment, which reduced arterial stiffness and oxidative stress in aged mice.

Vascular smooth muscle cells (VSMCs) have recently been discovered as important contributors to age-related increases in arterial stiffness. This increased VSMC stiffness is due to the direct relationship between VSMCs and endothelial cells. Endothelial cells regulate vascular tone mainly through the release of nitric oxide. This reduces active tone of VSMCs, which counteracts the increase in wall shear stress that occurs with both aging and high blood pressure. However, aging also leads to a decrease in the number of cells within the vascular wall due to a decrease in cell proliferation with age. Multiple mechanisms mediate the decrease of VSMCs with age, but most notably inflammation and calcification, which increase VSMC apoptosis. In humans, the VSMCs lost with aging are replaced by collagen fibers in the media of the arterial wall, resulting in increased vascular stiffness.

Osteoclasts, as an important component of the bone microenvironment, have always played an irreplaceable role in bone homeostasis. Abnormalities in osteoclast function can lead to abnormal bone resorption. If osteoclasts are hyperfunctional, they can cause degenerative bone diseases such as osteoporosis and osteoarthritis; if they are dysfunctional or declining, they can cause osteosclerosis. Drugs for bone-related diseases affect the process of bone resorption by osteoclasts in three main ways: differentiation, function, and apoptosis. Therefore, we summarize the biological characteristics of osteoclasts in terms of differentiation, apoptosis, behavior changes, and coupling signals with osteoblasts based on previous studies, in this review.

Although we have a more comprehensive understanding of osteoclasts, we still do not know the effects of various modulators on osteoclast behavior in the systemic as well as in the local environment and their mechanisms of action. Additionally, we still have a lot to learn about the processes that control osteoclast sexual dimorphic responses. Research of this phenomena are essential because they can shed light on the pathophysiology of metabolic bone disorders like osteoporosis and how individuals respond to treatment.

The identification of gene targets by understanding these mechanisms may lead to more effective treatments for metabolic diseases of the skeleton. As for coupling signals between osteoclast and osteoblast, rather than simply identifying potential coupling factors, it is time to move on to the next phase. It is imperative that we spend time understanding the kinds of mechanisms that drive the remodeling process, and identify the aspects of those mechanisms that can be used to intervene in human skeletal disorders. Furthermore, we think that interactions existing among macrophages, osteoclasts, and osteoblasts contribute to maintaining bone homeostasis. Therefore, we believe that pathological connections among these cells in disease states and their negative mechanisms will be a new field for further exploration.

This study describes seven epigenetic clocks for naked mole rats (NMRs), of which five are specific to NMRs (for different tissue types) and two are dual-species human-NMR clocks that are applicable to humans as well. The human-NMR clocks for chronological and relative age demonstrate the feasibility of building epigenetic clocks for different species based on a single mathematical formula. This further consolidates emerging evidence that epigenetic aging mechanisms are conserved, at least between members of the mammalian class.

On a phenotypic level, the NMRs appear to evade aging. Hence, we did not know whether they display epigenetic changes with increasing age. Our study clearly detected significant age-related changes in DNA methylation levels across the entire lifespan of the animal, even in relatively young animals. This contradiction between phenotypic and epigenetic aging could imply that age-related DNA methylation changes do not matter since they do not appear to correlate with any adverse functional consequences in NMRs. However, accelerated epigenetic aging has been correlated to a very wide range of pathologies and health conditions.

Alternatively, it could mean that while the NMR ages at a molecular level, as do all other mammals, it has developed compensatory mechanisms that counteract the consequences of these epigenetic changes. The NMR age-related CpGs that we identified, and the availability of epigenetic clocks, are valuable resources to resolve this question.

Further clues to NMR aging were also revealed from the three-way comparison of age-related CpGs between NMRs, primates, and mice. Although primates and NMRs are phylogenetically more distantly related than NMRs and the mouse, these relationships are not similarly manifested when it comes to longevity. Indeed, NMRs and humans are more akin to each other as they are both outliers with regards to lifespan expected from their adult size. Here, the three-way comparison revealed that the reason for the unusually long lifespans of NMRs and primates may lie in the coregulation of developmental and metabolic processes. Conversely, similarly regulated developmental genes between NMR and human may reflect neotenic features characteristic of these two species. Neoteny is defined as retention of juvenile features into adulthood. A shift towards longer development and retention of youthful tissue repair can lead to longevity.

The results of this systematic analysis demonstrate the substantial and growing global burden of cancer, with patterns of burden differing by sociodemographic index (SDI) quintile. In 2019, cancer-related disability-adjusted life years (DALYs) were second only to cardiovascular diseases in their contribution to global disease burden, and in the high SDI quintile, cancer overtook cardiovascular disease to become the leading cause of DALYs. Between 2010 and 2019, the number of new global cancer cases and deaths increased by 26.3% and 20.9%, respectively. However, the largest percentage increases in cancer incidence and mortality during the last decade occurred in the lower SDI quintiles, likely reflecting ongoing epidemiologic transitions, demographic shifts, and disparities in cancer prevention, care, and control.

While the absolute burden of cancer grew from 2010 to 2019, global age-standardized incidence rates remained similar at -1.1% and mortality rates decreased by -5.9%. These age-standardized mortality results suggest cautious optimism that some progress may have been made in early diagnosis and cancer treatment globally during the last decade.

However, inequities in the distribution and growth of cancer burden around the world diminish this potential advancement and suggest that an acceleration of efforts to effectively address cancer burden are needed. Of particular concern, recent progress in reducing age-standardized incidence and mortality rates seems concentrated in higher SDI locations, while both rates are still trending upward in lower SDI locations. The increasing age-standardized incidence and mortality rates in lower SDI quintiles may reflect several factors, including shifting population age structures, increasing capacity for diagnosis and registration of cancer cases and deaths, and changes in cancer risk factors, such as metabolic, behavioral, environmental, and occupational exposures.

Researchers analysed data from 6,551 adult Greenlanders and conducted experiments on mice. The results demonstrate that carriers of the genetic variation have what is known as sucrase-isomaltase deficiency, meaning that they have a peculiar way of metabolizing sugar in the intestine. Simply put, they do not absorb ordinary sugar in the bloodstream the way people without the genetic variation do. Instead, sugar heads directly into their intestine.

"Gut bacteria convert the sugar into a short-chain fatty acid called acetate, which in previous studies has been shown to reduce appetite, increase metabolism, and boost the immune system. That is most likely the mechanism happening here. Adult Greenlanders with the genetic variation have lower BMI, weight, fat percentage, and cholesterol levels, and are generally significantly healthier. They have less belly fat and might find it easier to get a six pack. It is amazing and surprising that a genetic variation has such a profoundly beneficial effect."

While the variation has clear health benefits for adult Greenlanders, it is problematic for their children. "Younger carriers of the variation experience negative consequences due to their different type of sugar absorption. For them, consuming sugar causes diarrhea, abdominal pain and bloating. Our guess is that as they age, their gut bacteria gradually get used to sugar and learn how to convert it into energy." The research team hope that they can use the results of their new study to lay the groundwork for developing new drugs that might one day be used to treat cardiovascular disease and obesity.

The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron.

In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide - stress-induced premature senescence (SIPS). Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state, represented by reduced glutathione/oxidized glutathione (GSH/GSSG), the mitochondrial morphology, and the proteins and membrane potential were determined.

Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.

This is the first study to our knowledge formally evaluating whether epigenetic age acceleration (EAA) in Horvath-multi tissue, Hannum, and Skin and Blood epigenetic clocks is associated with age-related macular degeneration (AMD) and important risk factor covariates including smoking status. We sought to address whether EAA is observed in the retinal pigment epithelium (RPE), as it is a primary site of AMD pathogenesis, and in whole blood, as the epigenetic clocks have been widely applied and validated in blood-derived genomic DNA.

EAA was not observed in AMD. However, we observe positive EAA in blood of smokers, and in smokers with AMD. In the RPE, we observed a marked negative EAA across all groups with no significant differences in EAA between AMD and normal samples using all three clocks. This result cannot be characterised as true negative age acceleration because of poor performance of the epigenetic clocks in RPE. The consistent poor correlation of predicted DNAm age with chronological age observed in the RPE markedly improved when analysing whole blood-derived genomic DNA data, explained by the datasets used to train each respective epigenetic clock.

Reasonable performance of each respective epigenetic clock in whole blood strengthens the observation of no association of EAA with AMD in blood, though this remains open to further investigation in the RPE, which can be addressed using a bespoke RPE epigenetic clock with greater predictive accuracy. Construction of a tissue-specific RPE clock is necessary for future studies to capture the specific epigenetic ageing processes in the RPE.

The sleep duration recommended by the National Sleep Foundation in 2015 was as follows: 7-9 hours in young people and adults, and 7-8 hours in elderly people. Excessive or insufficient sleep duration is disadvantageous for health. Previous studies have shown that sleep duration is associated with cardiovascular disease, cognitive decline, and metabolic syndrome, and aging.

Klotho protein is a multifunctional protein encoded by the klotho gene, and its expression level is associated with aging. It was found that mice lacking klotho suffer from premature aging syndrome, the lack of klotho in serum is also associated with heart aging, and decreased klotho levels are found in patients with various aging-related diseases, such as metabolic syndrome, cancer, and hypertension. In contrast, high level of klotho prolongs lifespan.

Aging is an inevitable process for human being, but the speed of aging is affected by many factors. Aging is affected by environmental, genetic, and epigenetic factors. On the other hand, the expression level of klotho may be potentially involved in the relationship between sleep duration and aging. Sleep disorders and aging are common public health problems, and the potential association between sleep duration and the anti-aging protein klotho is largely unexplored. Therefore, the purpose of this study was to investigate the potential association between them using the data of the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Our hypothesis is that sleep duration is associated with the serum anti-aging protein klotho concentration.

Sleep duration was non-linearly associated with the level of klotho protein in the serum, with a negative association between sleep duration and serum klotho concentration after adjusting for confounding variables. Serum klotho of the participants in the highest tertile (more than 7.5 hours) was 21.9 pg/mL lower than those in the lowest tertile (less than 5.5 hours). Thus our results revealed that people who sleep more than 7.5 hours per night have decreased levels of the anti-aging protein klotho in their serum, thus being more at risk of aging-related syndromes.

Accumulation of senescent cells can occur due to diminished clearance ability of the immune system or persistent exposure to senescence-inducing stimuli that produce more cells than can be cleared in time. Such accumulation can lead to a chronic inflammatory state in the surrounding tissue microenvironment, also referred to as inflammaging, that further promotes senescence in neighboring healthy cells.

Due to the deleterious effects of cellular senescence, the senescent cell has been the target of active research to tackle age-related pathologies either through the approach of seno-rejuvenation or senolytics. In a pioneering study done in 2011, researchers showed that by removing p16Ink4a-positive senescent cells, there was observable delayed tissue dysfunction and extended healthspan in a progeroid mouse model.

Senolytics refers to a class of pharmacological agents that eliminate senescent cells by inducing apoptosis. Compared to their healthy counterparts, senescent cells are highly resistant to apoptosis even in the presence of cellular stresses due to activation of pro-survival and anti-apoptotic pathways. One of the most common senolytics approaches is to inhibit pro-survival pathways such as those regulated by the BCL-2 protein family and PI3K/AKT pathway. Beyond the use of senolytic drugs, there is also increasing interest in the use of engineered immune cells for senolytics purposes, stemming from the observation on the role of immune system to clear senescent cells. In a recent study, developed chimeric antigen receptor (CAR) T cells as senolytic agents to target cells expressing urokinase-type plasminogen activator receptor (uPAR).

With the advent of population aging, aging-related diseases have become a challenge for governments worldwide. Sarcopenia has defined as a clinical syndrome associated with age-related loss such as skeletal muscle mass, strength, function, and physical performance. It is commonly seen in elderly patients with chronic diseases. Changes in lean mass are common critical determinants in the pathophysiology and progression of cardiovascular diseases (CVDs). Sarcopenia may be one of the most important causes of poor physical function and decreased cardiopulmonary function in elderly patients with CVDs. Sarcopenia may induce CVDs through common pathogenic pathways such as malnutrition, physical inactivity, insulin resistance, inflammation; these mechanisms interact.

Sarcopenia and CVDs are highly prevalent in the elderly and share common pathogenesis and interactions. Understanding their relationship is still in its initial stages, and more clinical and experimental data are needed. A large number of studies have shown that the progression of CVDs and the decline in muscle function will further worsen the patient's condition. By screening patients for sarcopenia at an early stage, establishing effective early detection methods and evaluation methods, and providing early and comprehensive interventions, the progression of the disease can be effectively delayed. Nevertheless more importantly, patients with CVDs should be rehabilitated as soon as possible to break the vicious cycle of sarcopenia and CVDs through scientific nutritional programs and training guidance. Effective treatment of either sarcopenia or CVDs can have a positive impact on another disease.

Ischemic-induced white matter injury is strongly correlated with the poor neurological outcomes in stroke patients. The transplantation of oligodendrocyte precursor cells (OPCs) is an effective candidate for enhancing re-myelination in congenitally dysmyelinated brain and spinal cord. Nevertheless, mechanisms governing the recovery of white matter and axon after OPCs transplantation are incompletely understood in ischemic stroke.

In this study, OPCs were transplanted into the ischemic brain at 7 days after transient middle cerebral artery occlusion (tMCAO). We observed improved behavior recovery and reduced brain atrophy volume at 28 days after OPCs transplantation. Moreover, our results identified that myelin sheath integrity and endogenous OPCs proliferation and migration were promoted after OPCs transplantation. In addition, the improvement of neurite growth and synaptogenesis after OPCs transplantation in ischemic brain or OPC co-cultured neurons, potentially through the upregulation of Netrin-1, was indicated by increased protein levels of synaptophysin and postsynaptic density protein 95.

In conclusion, our studies suggested that engrafted OPCs promoted the recovery after ischemic stroke by enhancing endogenous oligodendrogenesis, neurite growth, and synaptogenesis; the last two being mediated by the Netrin-1/DCC axis.

Here, we report the changes in gut microbial communities and their functions in mouse models during ageing and three rejuvenation procedures including co-housing of young and old mice, injection of young serum into old mice, and parabiosis between young and old mice. Ageing-induced changes in the composition of the gut microbiota are associated with various age-related disorders. However, the rejuvenating effects of altered gut microbiota on the presence of specific bacteria remain elusive. Here, we show the changes in key microbial communities and their functions during ageing and three rejuvenation procedures, and the increase in the healthy lifespan of aged mice by oral administration of Akkermansia muciniphila (AK).

Our results indicate that intestinal function, inflammation, and intestinal homeostasis of aged mice can be rescued by three rejuvenation intervention models. All rejuvenation procedures significantly increased the relative abundance of the butyrate producer Oscillospira in rejuvenated mice, while the abundance of the beneficial genus Akkermansia was significantly increased in rejuvenated mice only during co-housing and serum injection. In addition, we observed that the abundance of aged-specific genera, such as Paraprevotella, Prevotella, Odoribacter, Erysipelotrichaceae cc_115, Rikenellaceae AF12, and Helicobacter, was significantly decreased in all rejuvenated mice, suggesting that the relative abundance of young- and aged-specific bacteria was reversed in their young counterparts during the co-housing and parabiosis procedures.

It has been reported that a high abundance of Prevotella, Turicibacter, and Paraprevotella is associated with dysbiosis, chronic inflammation, and type 2 diabetes, suggesting that they increase the risk of inflammation. Defective intestinal function and inflammation in aged mice can be improved by gut microbiota remodelling, suggesting a causal link between age-related changes in the gut microbiome and age-dependent morbidities.

For effective anti-ageing, it is important to find an appropriate approach to specifically manipulate the microbiota. Although fecal microbiota transplantation has shown potential in the treatment of several diseases, it is a complex biological intervention and has intrinsic limitations, that is, it can use only feces from healthy donors that are free from diseases. In this study, we controlled the ageing-related phenotype by oral administration of a single microbe, AK. AK restores intestinal integrity by activating epithelial cells, thereby supporting the growth of other beneficial commensals.

Furthermore, our data shows that AK extends the healthy lifespan, as evidenced by the frailty index and restoration of muscle atrophy. Since the age-related inflammatory state is associated with a decrease in skeletal muscle size and function (sarcopenia), the decrease in inflammation caused by oral administration of AK may be involved in the restoration of muscle metabolic function.

Nicotinamide adenine dinucleotide (NAD) precursors and sirtuin-activating compounds (STACs) are becoming popular among longevity-minded individuals. The misguided conception that raising NAD or sirtuin activity can only have positive effects on human physiology should be considered erroneous and even deleterious. Hype exists around molecules that appear to extend life or slow down the aging process; however, little regard is given to the aberrant side effects or diseases that the upregulation of some molecules or overexpression of some proteins can cause, such as cancer.

Clearly NAD is used in all cells, including cancer cells, to produce energy. The findings of this review paper suggest that NAD supplementation should be discussed with a healthcare practitioner if you have a strong family history of cancer, have cancer, or have had cancer. Any given subject should first speak to their healthcare provider when considering NAD and possibly perform screening tests. However, NAD may fend off many other age-related diseases and prevent cancer from developing, so developing strategies to purge senescent cells from the body prior to NAD supplementation should also be considered.

The pursuit to blindly raise sirtuin activity in the quest for longevity may also produce counterproductive results and may be misguided. However, cancer cells like normal cells require the same cellular machinery to function, and this review does not find that NAD nor sirtuins cause cancer but may simply assist fuelling cancer where present. Where it is shown that sirtuin or NAD inhibition shows beneficial effects against cancer progression, it does not infer those elevated levels of sirtuins or NAD assist in cancer progression but are simply part of the cancer progression. Raising sirtuin or NAD activity may increase disease penetrance, and further research is required to understand the complex mechanisms at play.

Mesenchymal stem cell-derived exosomes have been under investigation as potential treatments for a diverse range of diseases, and many animal and clinical trials have achieved encouraging results. However, it is well known that the biological activity of the exosomes is key to their therapeutic properties; however, till date, it has not been completely understood. Previous studies have provided different explanations of therapeutic mechanisms of the exosomes, including anti-inflammatory, immunomodulatory, and anti-aging mechanisms.

The pathological effects of oxidative stress often include organ damage, inflammation, and disorders of material and energy metabolism. The evidence gathered from research involving animal models indicates that exosomes have antioxidant properties, which can also explain their anti-inflammatory and cytoprotective effects. In this study, we have summarized the antioxidant effects of exosomes in in vivo and in vitro models, and have evaluated the anti-oxidant mechanisms of exosomes by demonstrating a direct reduction in excessive reactive oxygen species (ROS), promotion of intracellular defence of anti-oxidative stress, immunomodulation by inhibiting excess ROS, and alteration of mitochondrial performance.

Exosomes exert their cytoprotective and anti-inflammatory properties by regulating the redox environment and oxidative stress, which explains the therapeutic effects of exosomes in a variety of diseases, mechanisms that can be well preserved among different species.