Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells.

Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age.

Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.

The immune system's white blood cells, which are produced in the bone marrow, mostly help to defend against bacteria and injury, but sometimes they can turn against the body - for example, in cardiovascular disease, their inflammatory aggression can harm arteries and the heart. The nervous system plays a role in controlling blood cell production through chemical messengers or neurotransmitters. This is important in people exposed to stress, where stress hormones controlled by the sympathetic nervous system may increase bone marrow activity and cardiovascular inflammation in response to the neurotransmitter noradrenaline. The sympathetic nerves have a counter player - the parasympathetic nerves, which slow down responses and bring about a state of calm to the body, mainly through the neurotransmitter acetylcholine.

Because acetylcholine can have a protective effect against inflammation and heart disease, researchers studied this neurotransmitter in the bone marrow. "When we looked into how acetylcholine acts on the production of blood cells, we found that it does the expected - it reduces white blood cells, as opposed to noradrenaline, which increases them. What was unexpected though was the source of the neurotransmitter acetylcholine." The team found no evidence in the bone marrow of the typical nerve fibers that are known to release acetylcholine. Instead, B cells, which are themselves a type of white blood cell (most known for making antibodies), supplied the acetylcholine in the bone marrow. "Thus, B cells counter inflammation-even in the heart and the arteries - via dampening white blood cell production in the bone marrow. Surprisingly, they use a neurotransmitter to do so."

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.

A variety of dietary interventions (i.e., calorie restriction, intermittent fasting, fasting mimetics, and dietary restriction) improve health and lifespan. Epidemiological data suggest that lowering dietary protein content supports metabolic improvements and resilience, while high protein intake correlates with increased mortality. Protein restriction (PR) is a form of dietary restriction in the absence of energy restriction that extends lifespan and improves general health measures in various organisms, including rodents, fruit flies, and yeast.

The PR-induced improvements on health naturally create an interest in the underlying cellular mechanisms. Most work has accentuated the ability of protein or amino acid restriction to engage a host intracellular nutrient-sensing pathways, including mTOR, GCN2, AMPK, autophagy, etc. However, several years ago our lab hypothesized that an endocrine effector signal of protein restriction might exist. This focus led to the discovery that the liver-derived hormone FGF21 is robustly induced by PR and that the deletion of FGF21 blocks adaptive metabolic responses to PR in young mice.

FGF21 increases energy expenditure, enhances glucose metabolism, and upregulates the thermoregulatory marker UCP1. FGF21 also crosses the blood-brain barrier, and several studies suggest that the physiological effects of FGF21 are mediated by the brain. Recent data from our lab indicate that FGF21/Klb signaling in the brain is essential for PR to increase energy expenditure, improve glucose homeostasis, and protect against diet-induced obesity in young mice.

Factoring in FGF21's key role in facilitating the metabolic response to PR in young mice, and that transgenic overexpression of FGF21 extends lifespan and improves insulin sensitivity, we hypothesized that increases in FGF21 might mediate the beneficial effects of long-term PR in aging animals. Here we demonstrate that, in male mice, FGF21 is required for the effects of PR on lifespan and metabolism. Indeed, mice that are FGF21 deficient are not only resistant to the health benefits effects of PR, but they also exhibit early-onset weight loss, increased frailty, and reduced lifespan when fed a low protein diet. Collectively, these data represent a suggest that FGF21 is essential for the pro-longevity effects of PR and highlight the power of a single endocrine hormone to coordinate metabolic and behavioral responses that improve metabolism and longevity.

Years ago, scientists thought that the adult mammalian brain was not able to repair and regenerate. But research has shown that some brain regions have the capacity of generating new neurons, a process called neurogenesis. The hippocampus region of the adult mammalian brain has the ongoing capacity to form new neurons, to repair and regenerate itself, enabling learning and memory and mood regulation during the adult life.

'We knew that neurogenesis has a 'master regulator,' a protein within neural stem cells called TLX that is a major player in the birth of new neurons. We did not know what stimulated TLX to do that. Nobody knew how to activate TLX. We discovered that a common fatty acid called oleic acid binds to TLX and this increases cell proliferation and neurogenesis in the hippocampus of both young and old mice."

While oleic acid also is the major component in olive oil, however, this would not be an effective source of oleic acid because it would likely not reach the brain. It must be produced by the cells themselves. The finding that oleic acid regulates TLX activation has major therapeutic implications. "TLX has become a 'druggable' target, meaning that knowing how it is activated naturally in the brain helps us to develop drugs capable of entering the brain and stimulating neurogenesis."

Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem cell and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known.

Here, we identify oleic acid as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.

A large body of work, carried out over the past decades in a range of model organisms including yeast, worms, flies and mice, has identified hundreds of genetic variants as well as numerous dietary factors, pharmacological treatments, and other environmental variables that can increase the length of life in animals. Current concepts regarding the biology of aging are in large part based on results from these lifespan studies. Much fewer data, however, are available to address the question of whether these factors, besides extending lifespan, in fact also slow aging, particularly in the context of mammalian models.

It is important to distinguish lifespan vs. aging because it is well known that lifespan can be restricted by specific sets of pathologies associated with old age, rather than being directly limited by a general decline in physiological systems. In various rodent species, for instance, the natural end of life is frequently due to the development of lethal neoplastic disorders: cancers have been shown to account for ca. 70-90% of natural age-related deaths in a range of mouse strains. Accordingly, there is a strong need to study aging more directly, rather than to rely on lifespan as the sole proxy measure for aging.

'Aging' is used as a term to lump together the processes that transform young adult individuals (i.e., individuals that have attained full growth and maturity) into aged ones with functional changes across multiple physiological systems, elevated risk for multiple age-related diseases, and high mortality rates. It is associated with the accumulation of a large number of phenotypic changes, spanning across various levels of biological complexity (molecular, cellular, tissue and organismal level) and affecting virtually all tissues and organ systems. Aging can hence be approached analytically by assessing age-dependent phenotypic change, from young adulthood into old age, across a large number of age-sensitive traits covering multiple tissues, organ systems and levels of biological complexity.

Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans.

We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging.

What makes some people predisposed to live and remain healthy much longer than others? That some persons reach an exceptional age has been recorded throughout history. It's tempting to write down such outliers as only the result of environment and behavior: for example, better-than-average nutrition, medical care, childcare practices, and hygiene, not to mention luck. But as average life expectancy continues to increase worldwide due to overall improvements in these and other factors, it's becoming clear that exceptional longevity and healthy aging tends to run in families. This suggests that genetic differences also play a role in assuring lifespan and life-long good health.

The Long Life Family Study (LLFS) focuses on families in the US and Denmark with multiple exceptionally long-lived members. It identifies, across two generations, which genetic, epigenetic, and other biological processes are associated with long life and healthy aging. Researchers now show that children born in exceptionally long-lived families differ from peers in their blood levels of biomarkers affecting the risk of type II diabetes: their genetic and epigenetic make-up help their body to remain responsive to insulin, even in old age. Their spouses - typically not born to exceptionally long-lived parents - tend to share these health- and lifespan-boosting biomarker levels. This implies that such family-specific beneficial biomarker levels aren't always inherited - you might also develop them if married to the right partner.

Among the children and their spouses, respectively 3.7% and 3.8% developed type II diabetes over the course of the study. This corresponds to a rate of 4.6 to 4.7 new cases of type II diabetes per 1000 person-years, about 53% lower than the rate among people between 45 and 64 years in the general US population. This implies that both the children and their spouses had a reduced risk of developing type II diabetes: one of the health and longevity benefits of being part of a long-lived family, either through descent or marriage.

Microglia are a group of neuroglia that account for 5-15% of total brain cells. As the resident-macrophage cells, microglia function as the main immune defense in the central nervous system (CNS). To sustain brain homeostasis, microglia continually surveille the brain microenvironment through their connections with neighboring cells and factors. During aging, microglia switch from resting state to activated state and contribute to the development of neurogenerative diseases. Activated microglia produce pro-inflammatory cytokines, and participate in regulating blood-brain barrier (BBB) integrity and synaptic plasticity in aged brain.

Recent studies suggested that the alterations of gut microbiota in the aged are associated with neurodegenerative diseases. Gut-brain axis indicates the complicated connections between gut and brain, which is crucial for microglial maturation and function. These findings pave a new way in attenuating and even reversing cognitive aging through microbiota-microglia axis intervention. In this review, we will review the composition of gut microbiota in aged individuals, depict the changes of microglia associated with aging and discuss neuroinflammation in the aged brain. We then summarize the mechanism of microbiota in regulating microglial function in the aged brain and highlight the role of microbiota-microglia connections in neurodegenerative diseases. This knowledge may enrich our understanding of the crosstalk between aging-related cognitive decline and the microbiota-microglia axis, facilitating the discovery of novel targets in restoring aging-related cognitive decline.

Kidney function tends to decline as people age, by as much as 50%, even in the absence of any identifiable kidney disease. This can be an important health issue for many elderly patients, increasing their risk of developing kidney failure and complicating treatment of many other medical conditions.

While lithium is a highly effective mood stabilizer and first-line treatment for bipolar disorder, scientists still don't know exactly how it works in the brain. However, researchers have found that one of the major molecular targets of lithium is GSK3-beta - an enzyme that is associated with cellular aging in the kidney and a decline in kidney function.

Researchers demonstrated that knocking out the gene responsible for producing GSK3-beta slowed kidney aging and preserved kidney function in animal models. Researchers then used lithium chloride to inhibit GSK3-beta, which achieved similar results. Mice had lower levels of albuminuria, or protein in the urine, improved kidney function and less cellular deficiency compared to a control group.

To further validate their findings, researchers also reviewed a group of psychiatric patients to assess their kidney health. Laboratory tests showed individuals who had received long-term treatment with lithium carbonate had better functioning kidneys than those who had not received lithium treatments, despite comparable age and comorbidities.

Ventricular arrhythmia­s can occur after a heart attack damages tissue, causing chaotic electrical patterns in the heart's lower chambers. The heart ends up beating so rapidly that it cannot support the circulation, leading to a lack of blood flow and, if untreated, death. Current treatment options for ventricular arrhythmia­s caused by heart attacks are far from ideal. These include medications with major side effects, implanted devices to provide an internal shock, and a procedure called radiofrequency ablation in which parts of the heart are purposely destroyed to interrupt disruptive electrical signals. Recurrence rates are, unfortunately, high for all of these.

Researchers sought to try a different approach in laboratory pigs that experienced a heart attack. They injected some of the laboratory pigs with tiny, balloon-like vesicles, called exosomes, produced by cardiosphere-derived cells (CDCs), which are progenitor cells derived from human heart tissue. Exosomes are hardy particles containing molecules and the molecular instructions to make various proteins, thus they are easier to handle and transfer than the parent cells, or CDCs. The animals were evaluated by MRI and tests to assess electrical stability of the heart. Four to six weeks after injection, the laboratory pigs that had received the exosome therapy showed markedly improved heart rhythms and less scarring in their hearts.

Scientists have developed a promising new method to combat the age-related losses in muscle mass that often accompany immobility after injury or illness. Physical therapy is often prescribed to promote healing after injury and immobility, she said. But studies show that muscle continues to deteriorate after the onset of exercise. Reactive oxygen species, a signal of inflammation and cellular dysfunction, accumulate in the muscles and impede the healing process.

In a previous study, researchers discovered that injections of support cells known as pericytes contributed to muscle recovery in young mice after a period of immobility. However, aged mice did not respond as well to the injections, and recovery was limited. In the new study, the team collected pericytes from the muscles of young, healthy mice and grew them in cell culture. They exposed the cells to hydrogen peroxide - a powerful oxidant that promotes the production of extracellular vesicles (EVs) containing factors that combat stress and enhance healing - and collected the EVs to use therapeutically.

The researchers injected their pericyte-derived EVs into the muscles of young and aged mice that had undergone a period of prolonged muscle immobility in one of their legs and were beginning to use those muscles again. The approach worked: The mice treated with the stimulated EVs recovered skeletal muscle fiber size in both young and aged mice. The study also revealed - for the first time - that EVs derived from muscle pericytes produced a variety of factors that may combat inflammation and oxidative stress.

Over the recent years, the fast-aging African turquoise killifish (Nothobranchius furzeri) has emerged as an excellent biogerontology model, Despite having a lifecycle of only a few months, killifish do age. They even age in a similar way as humans, presenting many of the well-described aging hallmarks, yet often magnified and occurring within a much shorter time frame. Interestingly, killifish appear to pay a price for their fast growth and aging. In contrast to zebrafish - that maintain their neuroreparative ability albeit regenerate less efficiently at old age - killifish completely lose their regeneration capacity at old age and are unable to fully recover from central nervous system (CNS) injury.

Using an optic nerve crush injury model in killifish of different ages, we indeed revealed that, in contrast to young fish, aged animals do not regain vision following damage. An inadequate intrinsic capacity of aged retinal ganglion cells (RGCs) to revert to a "regenerative state" as well as a growth-inhibiting neuron-extrinsic environment seem to contribute to this impairment, similar to what has been described for (young) adult mammals. We postulate that age-associated changes within neurons and their glial environment - already manifesting before damage occurs- negatively affect the regeneration potential of the killifish CNS, which then leads to a mammalian-like regenerative response upon injury.

With increasing age, we revealed reduced expression levels of growth-associated genes in retinal neurons, thereby affecting the intrinsic ability of RGCs to regrow their axons. Additionally, oxidative stress was shown to pile up in the aged killifish retina, which is known to lead to mitochondrial dysfunction and therefore very likely contributes to failure of the energy-demanding regenerative process. Next to neuron-intrinsic changes, we observed signs of astrogliosis, inflammaging, and a senescence-associated secretory phenotype upon aging, which might sensitize the old killifish CNS and result in growth-unfavorable glial reactivity upon injury.

The onset of astrogliosis and a chronic inflammatory status in the killifish CNS during physiological aging seems to result in a more extensive and extended glial reactivity upon nerve injury, which is known to be detrimental for regeneration in mammals. Strikingly, the exaggerated neuroinflammatory events then result in the formation of a long-term glial scar. In summary, it seems that explosive growth and/or fast aging eventually turns the killifish CNS into a regeneration-incompetent organ. By shifting its regenerative potential from high to low with increasing age and forming a glial scar following CNS injury, the killifish puts itself in the exceptional position of resembling (young) adult mammals when at old age.

The ultimate goal should be to "cure aging" - a phrase that many in the field are uncomfortable with. "What I mean by curing aging is having a risk of death that doesn't vary depending on how long ago you were born. A lot of scientists, even aging biologists, get a little bit squeamish when you say that. But I really do think that should be the fundamental aim of all medicine."

Using cancer as an example, most scientists working in that field would agree they are working towards an end goal of curing cancer. "I don't see why aging should be any different. At least the aspects of aging that cause frailty and discomfort and distress and pain and disease and all these horrible things we want to get rid of. I don't see why our goal shouldn't be to minimise that human suffering as far as possible. And to me, that means curing aging."

"How possible is that going to be? I'm absolutely convinced it's possible at some point. There's no law of biology that tells us we must age - we can look around the animal kingdom and see animals that don't age, they're negligibly senescent, they have exactly this risk of death that doesn't vary depending on how long ago they were born. The real question is, are we clever enough? Is our biotechnology advanced enough? And are we going to get lucky enough that it's going to happen in our generation?"

There is a hot topic in stem cell research to investigate the process of hematopoietic stem cell (HSC) aging characterized by decreased self-renewal ability, myeloid-biased differentiation, impaired homing, and other abnormalities related to hematopoietic repair function. It is of crucial importance that HSCs preserve self-renewal and differentiation ability to maintain hematopoiesis under homeostatic states over time. Although HSC numbers increase with age in both mice and humans, this cannot compensate for functional defects of aged HSCs.

The underlying mechanisms regarding HSC aging have been studied from various perspectives, but the exact molecular events remain unclear. Several cell-intrinsic and cell-extrinsic factors contribute to HSC aging including DNA damage responses, reactive oxygen species (ROS), altered epigenetic profiling, polarity, metabolic alterations, impaired autophagy, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor- (NF-) κB pathway, mTOR pathway, transforming growth factor-beta (TGF-β) pathway, and wingless-related integration site (Wnt) pathway.

To determine how deficient HSCs develop during aging, we provide an overview of different hallmarks, age-related signaling pathways, and epigenetic modifications in young and aged HSCs. Knowing how such changes occur and progress will help researchers to develop medications and promote the quality of life for the elderly and possibly alleviate age-associated hematopoietic disorders. The present review is aimed at discussing the latest advancements of HSC aging and the role of HSC-intrinsic factors and related events of a bone marrow niche during HSC aging.

YouthBio Therapeutics, a longevity biotechnology company, has announced today its emergence out of stealth mode. YouthBio focuses on developing gene therapies aimed at epigenetic rejuvenation, particularly with the help of partial reprogramming by Yamanaka factors. The company was founded in early 2021 by Yuri Deigin and Viet Ly who will serve as its CEO and CFO, respectively. Dr. João Pedro de Magalhães will serve as the company's CSO and Dr. Alejandro Ocampo will serve as lead research collaborator.

"I am very optimistic that in the next 10 years science will provide humanity with major breakthroughs that will enable us to add decades of healthy life to people. Partial reprogramming is something I was always excited about as having the potential to be one such therapy. I am thrilled to take its research and development to the next level with the help of amazing colleagues."

"Cellular reprogramming allows us to rejuvenate cells and reset their biological clocks. It is the most important technology available today for developing rejuvenation therapies, although it still needs to be fine-tuned for effective and safe applications. Exploiting cellular reprogramming to develop therapies for age-related diseases is extremely exciting and, if successful, may result in a paradigm shift in medicine."

The relationship between cellular senescence and autophagy is regarded as paradoxical. Autophagy activation in response to stress can successfully resolve it and thus spare the cell from entering senescence. However, if a cell does commit to senescence by other ways, autophagy becomes essential for cell survival and senescence establishment. Indeed, senescence-associated secretory phenotype (SASP) production imposes its burden on the secretory pathway, calling for increased proteostasis maintenance. In this regard, the first-ever demonstration of selective pharmacological elimination of senescent cells consisted in depriving therapy-induced senescent lymphoma of adaptive autophagy, leading to proteotoxic stress overload due to SASP expression.

Senolysis can actually be achieved by modulating autophagy in either direction: inhibiting autophagy can lead to proteotoxic stress in senescent cells producing an abundant SASP, and conversely, further activating autophagy can selectively kill senescent cells through type II autophagic cell death, i.e. excessive "self-eating".

Beyond bulk autophagy flux modulations to cope with increased secretory demands, finer processes appear to be at play in regulating proteostasis in senescence. Recently, it was shown that the stability of a defined set of proteins was regulated by selective autophagy in senescence through differential interactions with ATG8 family receptors. This selective autophagy network was fundamental in shaping several facets of the senescent phenotype, including SASP production and proteostasis. These studies pave the way for a more precise understanding of autophagy regulation in the physiology and the proteostasis of senescent cells, and the discovery of potentially more potent senolytic strategies.