Aging and age-related pathologies such as cancer are the consequence of deleterious changes in cells and tissues over time, including the progressive accumulation of DNA mutations. Calorie restriction (CR) can prevent many age-related changes, resulting in extended lifespan and reduced age-related pathologies. Several intracellular mechanisms through which CR can reduce the accumulation of mutations have been identified, including attenuating oxidative stress and enhancing DNA repair. In addition to these intracellular mechanisms, mechanisms that act at the tissue level may be at play. For example, in Drosophila, CR enhances intestinal cellular fitness through outcompetition of less fit cells, thereby preventing age-related decline of intestinal integrity. Whether related mechanisms upon CR in mammals exist that act at a tissue level is currently unknown.

The mammalian intestinal wall is a single layer of epithelial cells curved into so-called crypt-villus units. As a protective barrier against the external environment, this epithelial sheet is constantly exposed to potentially DNA-damaging substances. However, most mutated cells are naturally lost due to the highly dynamic self-renewing nature of the epithelium. Lgr5+ stem cells at the bottom of crypts are long-lived and can thus accumulate mutations. However, these Lgr5+ stem cells compete for niche occupancy, resulting in continuous replacement and loss of neighboring stem cells, which is often referred to as stem cell competition. As a result, most stem cells, including those carrying mutations, will be lost while the progeny of one stem cell ultimately replaces all other stem cells in the crypt. Therefore, mutations will only be retained in the intestine if they are acquired by stem cells that win the stem cell competition.

We and others have recently shown that the chance that a stem cell can outcompete its neighbors can be manipulated by lowering the number of stem cells through pharmacologically inhibiting WNT protein gradients. Mutated stem cells can more rapidly spread within crypts when there are less competing stem cells. Interestingly, CR has been shown to increase the number of stem cells in intestinal crypts. Here we find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.

In mice and humans, the hematopoietic system undergoes many functional and structural changes during aging, characterized by myeloid expansion, decreased immunity, and chronic low-grade inflammation. We hypothesized that these cellular changes contribute to hippocampal aging through the accumulation of pro-aging immune factors in old blood. Many of the age-related changes observed in old blood have roots in hematopoietic stem cell (HSC) aging.

We employed a heterochronic HSC transplantation model to test how exposure to an aged hematopoietic system contributes to hippocampal aging. Young (2 months) recipient mice were sublethally irradiated to destroy their native HSCs and transplanted with HSCs isolated from young (2 months) or old (24 months) donors, generating isochronic (Iso) and heterochronic (Het) HSC-reconstituted young mice. Blood chimerism was assessed by measuring the proportion of CD45.2 donor cells in CD45.1 recipient mouse blood by flow cytometry. Blood derived from old HSCs exhibited characteristic age-related myeloid bias 4.5 months post-transplantation. Animals showed no signs of illness or weight loss regardless of treatment.

To gain mechanistic insight into how the old hematopoietic system exerts its deleterious effects on cognition, we assessed peripheral immune cell infiltration into the hippocampus. Immunohistochemical identification of CD45.2+ hematopoietic cells in the dentate gyrus of CD45.1 recipient mice revealed low and equivalent levels of immune cell infiltration in Het and Iso HSC-reconstituted young mice. While we cannot exclude the possible contribution of these small numbers of peripheral immune cells, we hypothesized that the pro-aging effects of the old hematopoietic system are predominantly mediated through peripheral changes in circulating blood factors.

We performed unbiased proteomic analysis on blood plasma collected from Het and Iso HSC-reconstituted young mice 4.5 months post-transplantation. Using label-free mass spectrometry, we identified 22 factors that were differentially expressed between Het and Iso HSC-reconstituted young mice. Of these, the most significantly upregulated cytokine was cyclophilin A (CyPA, encoded by Ppia) - an intracellular protein that is secreted in response to inflammatory stimuli.

To test whether increasing systemic CyPA levels are sufficient to elicit age-related cognitive or cellular impairments, young (2 months) mice were intravenously injected with overexpression constructs encoding either CyPA or GFP control. Increased systemic levels of CyPA impair cognition in young mice, while inhibition of CyPA in aged mice improves cognition. Cumulatively, our data demonstrate that age-related changes in the hematopoietic system promote molecular, cellular, and cognitive hallmarks of hippocampal aging.

Notably, inhibiting CyPA has been demonstrated to be neuroprotective in a mouse model of amyotrophic lateral sclerosis. In humans, elevated cerebrospinal fluid CyPA levels have recently been associated with cognitive impairments in Alzheimer's disease patients expressing apolipoprotein E4. Moreover, in humans elevated CyPA plasma levels accompany a number of inflammatory age-related diseases, including diabetes, and cardiovascular disease. In these studies, CyPA plasma levels were also found to be elevated with aging. While little is known about the role of CyPA in aging, recent proteomic analysis using mass spectrometry has identified CyPA as part of the senescence-associated secretory phenotype (SASP). Ultimately, our data identify the aged hematopoietic system, and downstream circulating immune factors, as potential therapeutic targets to restore cognitive function in the elderly.

Deep in the labs at the University of Exeter's College of Medicine and Health (CMH), a new company is emerging. Co-founded by Professor Lorna Harries, SENISCA is developing "senotherapeutic interventions" that reverse cellular senescence. Through modulation of RNA splicing, the company has developed a way to effectively turn back the aging clock in old cells and is working on developing new treatments for the diseases and aesthetic aspects of aging.

"I'm an academic, but my ambition also has always been that anything that we discover that shows clinical potential is pursued and followed through to the clinic. Having shown that splicing regulation declines during aging, the question for me then was - what happens if you turn it back on?" This question led Harries to the study, which showed that cells could not only be brought out of senescence but that, by doing so, the cells were also rejuvenated.

"When we did that, we were utterly, utterly amazed. While there had been research that showed aging could be reversed in animal models by removing senescent cells, this was different. So we're not removing senescent cells, we are rejuvenating them. The cells regain pretty much all of the features of young cells. They're still old cells, but they're not senescent, so they're not throwing out inflammatory proteins, which is what's doing the damage to our bodies. We learned that yes, you can target those pathways and you can reverse senescence. The molecules were used to do that were already in the clinic as anti-cancer agents, so we knew they were safe and specific, so that proved that we'd found the right pathway."

Our founders have discovered that levels of splicing factors change during ageing, compromising our ability to carry out this 'fine tuning' of gene expression. This is a fundamental reason why cells become senescent. Compromised molecular resilience is a major cause of the ill health and frailty that accompanies ageing. We have demonstrated that restoration of splicing factor levels to those seen in younger cells is able to effectively turn back the ageing clock in old cells, bringing about reversal of senescence.

At SENISCA, we are taking a two-faceted approach for modulation of splicing factor levels. Firstly, we are identifying small molecules capable of restoring splicing factor levels. Secondly, we are targeting the genes that control splicing factor levels directly. Both approaches will reset splicing factor levels and reverse senescence. We anticipate that understanding the molecular basis of rejuvenation will highlight new treatments for the diseases and aesthetic aspects of ageing. More importantly, it is likely that preventative approaches based on rejuvenation will be developed reducing both disease incidence and severity.

Microglial activation is implicated in the pathogenesis of multiple neurodegenerative diseases. Under physiological conditions, microglia are in a resting state characterized by ramified morphology, and they function as homeostatic keepers of the central nervous system. Resting microglia are not dormant; their processes are constantly and actively scanning a defined territory of brain parenchyma. After they have been exposed to stimulatory signals, microglia undergo various degrees of activation, such as changing their morphology, gene expression, and functional behavior. Depending upon the type, intensity, and duration of the exposure to the stimuli, activated microglia can be neuroprotective or neurotoxic. Activated microglia can release various inflammatory cytokines and toxins that together might injure or even cause neuronal death.

Brain-derived neurotrophic factor (BDNF), a versatile member of the neurotrophin family, is widely and highly expressed in the brain and is a chief regulator of axonal growth, neuronal differentiation, survival, and synaptic plasticity. In the central nervous system, BDNF and downstream prosurvival pathways have been demonstrated to protect neurons from damage and enhance neuronal network reorganization after injury. It has also been reported that BDNF treatment could reduce degrees of microglial activation in certain brain injury models, albeit these responses were considered a consequence of reduced neuronal injury and death elicited by BDNF. The direct effect of BDNF on microglia has rarely been explored.

This study aimed to characterize the role of BDNF in age-related microglial activation. Initially, we found that degrees of microglial activation were especially evident in the substantia nigra (SN) across different brain regions of aged mice. The levels of BDNF and TrkB in microglia decreased with age and negatively correlated with their activation statuses in mice during aging. Interestingly, aging-related microglial activation could be reversed by chronic, subcutaneous perfusion of BDNF. Peripheral lipopolysaccharide (LPS) injection-induced microglial activation could be reduced by local supplement of BDNF, while shTrkB induced local microglial activation in naïve mice. Thus in conclusion, decreasing BDNF-TrkB signaling during aging favors microglial activation, while upregulation BDNF signaling inhibits microglial activation via the TrkB-Erk-CREB pathway.

Cdc42 is involved in multiple and diverse functions of eukaryotic cells, including actin cytoskeleton reorganization, cell polarity, and cell growth. The activity of Cdc42 is significantly elevated in blood of elderly humans and in several tissues of aged C57BL/6 mice. We recently identified a specific small-molecule inhibitor of Cdc42 activity termed CASIN. Administration of CASIN in vivo did not show signs of toxicity. Previously, we reported that a brief ex vivo exposure of aged hematopoietic stem cells (HSCs) to CASIN that reduced the activity of Cdc42 in aged cells to the level found in young cells resulted in long-lasting youthful function of HSCs in vivo, likely due to epigenetic remodeling of aged cells upon modulation of Cdc42 activity. Consequently, we hypothesized that maybe a short-term systemic reduction of Cdc42 activity in aged animals in vivo might be also beneficial for lifespan, as an elevated activity of Cdc42 upon aging is causatively linked to a shorter lifespan in mice.

To determine whether a short-term systemic CASIN treatment of aged animals might indeed influence lifespan, we administered CASIN via intraperitoneal injection every 24 hours for 4 consecutive days to 75-week-old female C57BL/6 mice. 4 days of consecutive injections did not induce acute toxicity, and as well, none of the treated mice died within 4 weeks after CASIN injections, rendering chronic toxicity issues unlikely. Quantification of Cdc42 activity 24 hours after the last injection on day 5 demonstrated a reduction of Cdc42 activity in aged bone marrow cells to the level seen in young, confirming that CASIN is indeed reducing Cdc42 activity after a systemic in vivo treatment. Notably, aged mice treated with CASIN for only 4 consecutive days showed extension of their average and also maximum lifespan.

We performed analyses to investigate the extent to which aging-associated inflammatory cytokines in serum of aged mice were affected by CASIN treatment. Data showed a marked increase in the concentrations of INFγ, IL-1β, and IL-1α on aging and the concentrations for these cytokines were similar to concentrations in young animals upon CASIN treatment of aged mice. It is thus a possibility that a reduction in the concentrations of these cytokines upon CASIN treatment might contribute to the increase in lifespan observed in these animals.

Previously, the methylation status of CpG sites within the genes Prima1, Hsf4, and Kcns1 was shown to qualify as likely predictor of biological age of C57BL/6 mice. Applying this C57BL/6-trained DNA methylation marker panel to blood cells from aged animals treated with CASIN 9 weeks after treatment, we observed that epigenetic age predictions did not correlate anymore to the chronological age as in aged control animals, but resulted in a biological age prediction that was on average 9 weeks younger than their chronological age. These data imply that epigenetic changes underlie the extended longevity of aged CASIN-treated mice, while reinforcing the necessity to mechanistically validate tissues, cells, and biological pathways involved in the extension of longevity.

People who received at least one flu vaccination were 17% less likely to get Alzheimer's disease over the course of a lifetime, according to new research. "Because there are no treatments for Alzheimer's disease, it is crucial that we find ways to prevent it and delay its onset. About 5.8 million people in the United States have this disease, so even a small reduction in risk can make a dramatic difference. We began our study by looking for ways we could reduce this risk."

"Our role was to sort through enormous amounts of de-identified patient data in the Cerner Health Facts database to see whether there are drugs that could be repurposed to reduce the risk of Alzheimer's disease. Once we identified the flu vaccine as a candidate, we used machine learning to analyze more than 310,000 health records to study the relationship between flu vaccination and Alzheimer's disease."

The research team also found that more frequent flu vaccination and receiving vaccination at younger ages were associated with even greater decreases in risk. "One of our theories of how the flu vaccine may work is that some of the proteins in the flu virus may train the body's immune response to better protect against Alzheimer's disease. Providing people with a flu vaccine may be a safe way to introduce those proteins that could help prepare the body to fight off the disease. Additional studies in large clinical trials are needed to explore whether the flu shot could serve as a valid public health strategy in the fight against this disease."

The oldest trees on Earth have stood for nearly five millennia, and researchers have long wondered to what extent these ancient organisms undergo senescence, physically deteriorating as they age. A recent paper studying ginkgoes, one of the world's longest-lived trees, even found that they may be able to "escape senescence at the whole-plant level," raising questions about the apparent lack of aging in centuries-old trees. However, researchers argues that although signs of senescence in long-lived trees may be almost imperceptible to people, this does not mean that they're immortal.

"When we try to study these organisms, we're really astonished that they live so long. But this doesn't mean that they're immortal. They live so long because they have many mechanisms to reduce a lot of the wear and tear of aging. They have limits. There are physical and mechanical constraints that limit their ability to live indefinitely." However, due to the difficulty of conducting research on trees with such long lifespans, little is known about what the process of senescence looks like. Simply finding enough millennial trees to study can be challenging. "When a species of tree can live for five millennia, it's very difficult to find even two trees that are between two and five millennia." For these long-lived trees, dying of senescence is a possibility, but the probability of dying from other causes is significantly higher.

Trees have a variety of ways to reduce their chances of death from aging alone, from compartmentalizing risk in complex branch structures to "building life on death" by growing new shoots from trunks composed of 90% nonliving biomass. But researchers maintain that even though long-lived trees can survive for millennia through these methods, the stress associated with aging, although little, will ultimately prevent immortality.

Alzheimer's disease begins with a silent phase lasting two decades or more during which amyloid plaques slowly collect in the brain without causing obvious cognitive problems. For decades, researchers have been searching for an easy and affordable way to identify people in the so-called preclinical stage so that, once effective drugs are available, they could be treated and, ideally, never develop symptoms at all. Positron emission tomography (PET) brain scans can identify people with amyloid plaques, but they are too time-consuming and expensive to be widely used for screening or diagnosis.

Researchers previously had discovered that people with amyloid plaques tend to have certain forms of tau in the cerebrospinal fluid that surrounds their brains and spinal cords. Sampling the cerebrospinal fluid requires a spinal tap, which some participants are reluctant to undergo, but proteins in the cerebrospinal fluid can spill over into the blood, which is easier to obtain. If these specific forms of tau could be found in a person's blood, they reasoned, that might be an indication that the person has the consequences of amyloid plaques in his or her brain.

Researchers analyzed blood samples and brain scans from 34 people participating in Alzheimer's research studies. Nineteen of the participants had no amyloid in their brains, five had amyloid but no cognitive symptoms, and 10 had amyloid and cognitive symptoms. The researchers used mass spectrometry to identify and measure the different forms of tau in the blood samples. They found that levels of a form of tau known as phosphorylated tau 217 correlated with the presence of amyloid plaques in the brain. People with amyloid in their brains had two to three times more of the protein in their blood than people without amyloid. These high levels were evident even in people with no signs of cognitive decline.

To verify their findings, the researchers repeated the analysis in a separate group of 92 people: 42 with no amyloid, 20 with amyloid but no cognitive symptoms, and 30 with amyloid and symptoms. In this analysis, levels of phosphorylated tau 217 in the blood correlated with the presence of amyloid in the brain with more than 90% accuracy. When the researchers looked only at people with no cognitive symptoms, blood levels of phosphorylated tau 217 distinguished those in the early, asymptomatic stage of Alzheimer's disease from healthy people with 86% accuracy.

Hair growth depends on the health of dermal papillae (DP) cells, which regulate the hair follicle growth cycle. Current treatments for hair loss can be costly and ineffective, ranging from invasive surgery to chemical treatments that don't produce the desired result. Recent hair loss research indicates that hair follicles don't disappear where balding occurs, they just shrink. If DP cells could be replenished at those sites, the thinking goes, then the follicles might recover.

Researchers cultured DP cells both alone (2D) and in a 3D spheroid environment. A spheroid is a three-dimensional cellular structure that effectively recreates a cell's natural microenvironment. In a mouse model of hair regeneration, the team looked at how quickly hair regrew on mice treated with 2D cultured DP cells, 3D spheroid-cultured DP cells in a keratin scaffolding, and the commercial hair loss treatment Minoxidil. In a 20-day trial, mice treated with the 3D DP cells had regained 90% of hair coverage at 15 days.

"The 3D cells in a keratin scaffold performed best, as the spheroid mimics the hair microenvironment and the keratin scaffold acts as an anchor to keep them at the site where they are needed. But we were also interested in how DP cells regulate the follicle growth process, so we looked at the exosomes, specifically, exosomal miRNAs from that microenvironment." Exosomes are tiny sacs secreted by cells that play an important role in cell to cell communication. Those sacs contain miRNAs, small molecules that regulate gene expression. The team measured miRNAs in exosomes derived from both 3D and 2D DP cells. In the 3D DP cell-derived exosomes, they pinpointed miR-218-5p, a miRNA that enhances the molecular pathway responsible for promoting hair follicle growth. They found that increasing miR-218-5p promoted hair follicle growth, while inhibiting it caused the follicles to lose function.

Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals.

In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression.

Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.

Dopaminergic neurons, a critical modulatory system in the brain, are greatly affected by age, but it is unclear whether it can impact the aging process in animals. During the course of studying a putative scaffolding protein, Mask, a novel role was discovered for dopaminergic neurons in regulating longevity and aging in fruit flies. Overexpressing Mask in dopaminergic neurons leads to a ∼40% increase in lifespan in flies. This effect seems to be specific to the dopaminergic neurons, as overexpressing Mask in neither the entire body nor the nervous system (neurons or glial cells) showed significant effects on the lifespan.

Although the dopaminergic system provides essential modulation on various behaviors and physiological functions, flies devoid of dopamine in their brains and worms lacking the rate-limiting enzymes for dopamine synthesis live a normal lifespan. These results suggest that dopamine systems is not required to drive normal aging. Overexpressing Mask in specific dopaminergic neurons possibly induces a gain-of-function cellular effect, which consequently confers a beneficial outcome on aging and longevity.

The lifespan extension induced by Mask-overexpressing is accompanied by sustained adult locomotor and fecundity in the long-lived flies; and other physiological functions in the adult flies include food intake and insulin production in the brain are not consistently altered by overexpressing Mask in either group of dopaminergic neurons. The recent finding that Mask promotes microtubule dynamics in fly larval motor neurons and body wall muscles led to the postulation that altered microtubule dynamics in the Mask-expressing dopaminergic neurons is the key mediator. Overexpressing the Kinesin heavy chain Unc-10427 or knocking down a component of the Dynein/Dynactin complex, p150Glued28 are two interventions that have been previously shown to impact MT dynamics. Overexpressing Unc-104 or moderately reducing p150Glued level in the same groups of dopaminergic neurons also extend lifespan in flies, thus demonstrating that increasing MT dynamics and reducing microtubule stability in dopaminergic neurons is sufficient to induce lifespan extension in flies.

Aging is characterized by the progressive deterioration of the body's physiological function, which leads to decreased health, increased incidence of degenerative diseases and, finally, a progressive increase in the risk of death. Aging is classically approached as an inevitable phenomenon whose problems are treated in a timely and palliative way, aiming only to minimize the suffering of the elderly or extend their life span. In addition, these illnesses, usually manifested by chronic diseases associated with aging, tend to be treated individually. That is, individuals with cancer will be treated to eliminate the tumor, while diabetics will be treated with drugs to lower blood glucose levels. As much as it is obvious that these people should be treated, these treatments are still palliative, since even with the cure of one of these diseases, the elderly individual continues to be at an increased risk for other diseases that will inevitably kill them. That is why the main health agencies in the world started to approach aging itself as a clinical entity that deserves to be treated as such. Not by chance, the first clinical study that aims to delay aging itself has recently started.

The impact of having aging as a target for treatment is enormous, not only because aging is the main risk factor for death among humans, but also because it tends to be one of the main expenses of elderly individuals and governments, and it is potentially a major cause of social inequality. If health systems maintain their current policy, public health costs are expected to double by 2050, creating a burden that many countries will not be able to sustain. In addition to health gains, intervening with aging would represent savings of approximately 7 trillion over 50 years in the US alone, while disease retardation scenarios would lead to minimal savings, since the risk of individuals acquiring other chronic disabling diseases remain.

But is it even possible to delay the aging process itself, or even reverse it as some propose? In 2016, it was suggested that there is a maximum limit to human life span, and that this limit is around 115 years old. This article, however, has been challenged in regard to the statistical analysis, and some are convinced that the proposed limit on human longevity proposed is not real. In fact, a more recent study of Italian centenarians showed that, surprisingly, the risk of death stops increasing with time when individuals reach the age of 105 years. The progressive increase in the risk of death is what characterizes the aging process in living beings. Thus, eliminating this increase means, in practice, that aging stops happening after a certain age. According to the study, at 105 years of age, the chance of death remains fixed at around 50% per year. This leads to the conclusion that at a given moment the balance between damage and repair stabilizes, preserving vital functions as they are, ceasing, however without reversing, the aging process. Although the estimates are still up for debate, the question remains: if it is possible to stabilize and mitigate the aging process at some point in life, why wouldn't it be possible to do it at a younger age?

Evidence that indicates this is possible is abundant in nature. There are several species that show negligible aging, i.e. which do not present an increased risk of death (or hazard rate) with age. For example, some species of turtles live for decades and show no signs of senescence. The Greenland shark is yet another vertebrate of extreme longevity and can live more than 400 years. Even among closer species and with similar habits, the lifespan can vary greatly. The naked mole-rat is a rodent that lives up to 30 years and practically does not develop cancer, unlike other rats and rodents that live a maximum of 5 years. Some species, such as the hydra, are even considered "immortal", or "amortal", because they do not die from causes related to aging. Even in humans, there are cells that can be considered amortal, such as germline cells. In other words, nature offers us examples of how aging and lifespan can be controlled. Looking at these examples, understanding how individual's senescence rate is determined, and proposing strategies to delay aging are the goals of a growing field called biogerontology.

There is ample need to communicate fresh facts, principles and arguments around aging research and longevity technology opportunities within the European Union, with the single message that only these new technologies will provide a long-term solution to the problems presented by aging and general health. The last decade yielded a complete change of the paradigm around the understanding of the main hallmarks of aging and the malleability of the overall aging process. Building upon accumulating research in the previous decades, aging research has gone completely mainstream, and the paradigm of translational geroscience has gained strong supporters working on interventions directly targeting the root causes of biological aging to prevent - the biggest killer - age-associated diseases, and to extend healthy lifespan, aka healthspan, significantly.

Cross-European single issue longevity politics has an actual birth date, or rather period, the Members of the European Parliament elections of 2019. That is when multiple actors, in different countries stood at the elections focusing on the issue of working towards preventing age-associated diseases with healthy longevity technologies. Let me highlight here a dedicated, single-issue, one of its kind, political party, the German Party for Health Research and myself who stood as an independent candidate in the East of England Region. We got 0.2% of the votes with an almost zero budget, virtually unknown, meaning 1 in 500 voters thought the mission and programme are worth their votes.

The European Longevity Initiative (ELI) is a loose association of mainly EU citizens and residents coming together to form a healthy longevity advocacy group particularly targeting EU level legislation and EU wide public. Its associates are currently covering the following EU countries: Germany, Slovenia, France, Czech Republic, Belgium, Hungary, Greece, Austria, Poland. Moreover, current ELI associates are representatives of at least six existing European longevity advocacy groups. (1) The already-mentioned German The Partei für Gesundheitsforschung - The Party for Health Research; (2) LongevityForum.eu, funded by longevity supporters in the Czech Republic; (3) UK-based Longevity International running the pioneering All Party Parliamentary Group (APPG) for Longevity in the UK; (4) International Institute of Longevity based in Poland and Liechtenstein; (5) Društvo za vitalno podaljševanje življenja Slovenije - Slovenian society for vital life extension; (6) Heales Société pour l'Extension de la Vie - The Healthy Life Extension Society, based in Belgium.

Mitochondria frequently undergo coordinated cycles of fusion and fission (known as mitochondrial dynamics) to properly adjust the shape, size, and cellular distribution of the organelle to meet specific cellular requirements. Fusion produces elongated mitochondria by respectively joining the outer and inner membranes of two mitochondria. The closely related Dynamin-related GTPases, Mfn1 and Mfn2, mediate outer membrane fusion, while Opa1 is integral for fusion of the inner membrane. On the other hand, excessive mitochondrial fission produces fragmented mitochondria and is mediated by another Dynamin-related GTPase, called Drp1. Drp1 is recruited by its receptors on the outer membrane and oligomerizes along the mitochondrial constriction site to constrict the organelle and induce scission.

Mitochondrial dynamics are known to influence several mitochondria-dependent biological processes, such as lipid homeostasis, calcium homeostasis, and ATP production. Recent studies have also proposed a role for mitochondrial fusion and fission in regulating stem cell fate. In one interesting example, murine neural stem cells were shown to exhibit elongated mitochondria, and depletion of Mfn1 or Opa1 impaired their self-renewal. Despite tantalizing observations such as these, the overall impact of mitochondrial dynamics in aging stem cells and the mechanisms by which mitochondrial dynamics might affect stem cell function remain unclear.

Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging-related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator Drp1 are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition.

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgA mitochondrial DNA 'mutator' mouse.

In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgA mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgA mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA cells.

Finally, application of an exercise intervention to a subset of PolgA mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.