Fight Aging! Newsletter, November 22nd 2021

One of humanity's greatest success stories of the past century is the increase in global life expectancy as a result of the social and medical advancements that have dramatically improved basic living conditions and reduced vulnerability to infectious diseases. However, longer lives haven't fully translated into healthier lives, and as we grow older the likelihood that we will live with debilitating chronic illness rises significantly. Beyond unacceptable personal suffering, this places extreme pressure on both health-care systems and the economic models of advanced economies.

However, a new frontier of science is emerging - longevity research, also referred to as geroscience - that is helping us understand the underlying biological mechanisms of how and why we age, with the potential to develop treatments that delay, prevent or even reverse the onset of ageing and multimorbidity. In short, the nature and speed of the ageing process, and the aches and pains that accompany it, may not be inevitable. If we can successfully intervene to ensure ageing is healthy for as long as possible, then the potential gains in personal, public and economic health would be enormous.

In this paper, we examine the public-health and economic imperative to act, look at some of the most promising areas of innovation in longevity research across academia and industry, and propose practical actions that governments should take to invigorate this critical but under-resourced area of science. Given the profound implications, we believe governments should set ambitious targets: the UK and other advanced economies should aim for "30 in 30" - to increase healthy life expectancy by 30 years (to approximately 95 years) by 2050. While our work is international in scope, we also include a case study on how the UK can play a global leadership role in longevity research and development. With its world-leading academic institutions, strong life-sciences industry, access to vast NHS data sets and a global financial hub in London, the UK is already primed to become a global leader in this nascent field.

Fisetin and quercetin (Q) are plant-derived flavonoids that offer cytoprotection against cellular stress and act as anti-inflammatory, chemopreventive, chemotherapeutic, and senotherapeutic agents. Dasatinib (D) is a tyrosine kinase inhibitor used to treat leukemia and is routinely used in combination with Q to improve the senotherapeutic potency. Fisetin and D+Q selectively clear senescent cells, thereby delaying aging-associated disorders and improving healthspan and lifespan. This has been observed after reducing senescent cell burden in progeroid mice or in 22-24 month old C57BL/6 mice. Moreover, deletion of senescent cells from the brain genetically or pharmacologically with senolytic drugs led to functional improvements in mouse models of neurodegenerative diseases such as Parkinson's and Alzheimer's=. These studies have shown senolytics can reduce senescent cell burden and have positive impacts on animals with accelerated aging, advanced age, or neurodegenerative disorders. Accordingly, senotherapeutics are currently marketed as anti-aging therapies where young, healthy adults can take these products as dietary supplements.

However, less is known regarding their anti-aging effects of these compounds when administered prior to significant senescent cell accumulation. Thus, the experiments were designed to examine the long-term effects of monthly oral treatment with Fisetin or a D+Q cocktail when administered to C57BL/6 mice starting at 4 months age. Since aging alters numerous biological functions, we examined morphological, metabolic, and cognitive components that are known to be affected by senescent cell accumulation. The results presented here indicate that monthly administration of Fisetin or D+Q had sexually dimorphic effects which also depended on treatment type in C57BL/6 mice.

Our study indicates that both age and sex may also determine the therapeutic outcomes of senolytic treatment. When the treatment was started at 4 months of age, before the reported senescent cell accumulation, Fisetin had beneficial effects in male mice while a D+Q cocktail had adverse consequences in female mice. Fisetin treated male mice had reduced senescence-associated secretory phenotype (SASP), enhanced glucose and energy metabolism, improved cognitive performance, and increased hippocampal expression of adiponectin 1 receptor and glucose transporter 4. D+Q treated females had increased SASP expression along with accumulation of white adipose tissue, reduced energy metabolism, and cognitive performance.

These observations provide novel information with translational relevance. First, senolytic drugs can be taken at an age before significant senescent cell burden to reduce or prevent their prevalence later in life. Second, males and females have differential responses to the same senolytic treatment when initiated at younger ages. Third, a particular senolytic treatment may have beneficial, negligible or detrimental effects depending on the age, sex, or disease. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation.

Five patients participated in the study and were classified as having mild or moderate dementia. All patients performed witnessed informed consent and provided information from their primary doctor including diagnosis, brain images, and bloodwork. All accepted to participate in genetic testing and telomere testing. Pre-treatment Folstein cognitive testing was performed on all patients and repeated post treatment at intervals of approximately once a month following the initial treatment. Pre-treatment medical laboratory blood analysis was performed and repeated post treatment along with doctor office visits at 3, 6-, 9-, and 12-month periods. Pre-treatment brain Magnetic Resonance Imaging (MRI) was performed and repeated 10 months post treatment.

Recent reports of fatalities in the ASPIRO (AT132) trial highlighted the potential dangers of AAV therapy regarding dose limitations and immunological issues. In the AT132 trial, large doses (1E14 vg/kg or higher) of AAV administered via an intravenous route in patients with preexisting hepatic disease resulted in the death of 4 participants. Mechanisms felt to be causal in these deaths are direct hepatic toxicity from the large viral load as well as stimulation of an aggressive immune response.

Regional AAV gene transfer therapy is felt to be less risky due to the lower does utilized or required, minimal viral load to the liver, and that the regional therapy is often delivered to immune privileged areas like the ocular globes or the central nervous system. The patients in this study received the equivalent of 1/10000 of the dose of the patients in the AT132 trial. Additionally, in this case the dosing was regional rather than intravenous. This extremely low dose essentially minimized the risk of hepatoxicity to almost zero. Additionally, the regional delivery to the CNS minimized the risk of a significant humoral response thereby maximizing the potential for cell transduction.

No short term or long term clinical of laboratory complications were observed or identified. Monitored serum chemistry, electrolyte, and hematological values remained stable throughout the follow-up time. No serious adverse effects such as a visible or laboratory detected innate or humoral immune response was observed or reported. Hepatic function, as monitored by clinical laboratory values, remained within normal parameters, showing no evidence of hepatic insult. The treatment was well tolerated with only brief minimal physical discomfort at the injection site.

Pretreatment brain MRI compared to post treatment Brain MRI demonstrated no significant changes. Our telomere analysis before and after treatment demonstrated evidence of increased telomerase function. The median and the short telomeres were measurably elongated. Reduced biological age was seen in 4 of 5 participants. Cognitive assessment before and serial cognitive testing after treatment demonstrated a rapid improvement in cognitive function during the first 3.5 months after which the improvement slowed until it leveled off at five months. Thereafter there is a slight decrease slope in the average test score with an average drop of 0.07 points per month. Given that Patients with Alzheimer's dementia typically show an annual decline of 3 points on the on the Folstein test, our results indicate that the AAV hTert and Klotho gene transfer therapy was successful, and the effects of that gene therapy reversed some of the dementia pathology.

Multipotent mesenchymal stromal cells (MSCs) are a heterogeneous population of cells isolated from bone marrow and other tissue stroma that have immunosuppressive and anti-inflammatory properties. In many animal models of disease, MSCs have demonstrated therapeutic efficacy regardless of major histocompatibility complex or species barriers. It remains unclear how MSCs isolated from different tissues or species could exert therapeutic effects on such a wide range of unrelated diseases.

The current consensus is that therapeutic applications of MSCs are based on their secretion of a wide array of cytokines, chemokines, and subcellular particles5. However, MSCs do not engraft and there is little evidence that these cells even survive infusion or injection. Studies tracking MSCs after intravenous administration reported lung entrapment, upregulation of apoptosis-associated genes and presence of apoptotic bodies in the lungs. Only dead MSCs were detected in the lungs and liver 24 hours after administration. In a graft versus host disease study, it was demonstrated that only patients whose immune cells were able to induce apoptosis in MSCs responded to MSC therapy, suggesting that MSC apoptosis may contribute to clinical response.

In the current study, we generated apoptosis-refractory human MSCs to test whether inhibiting cell death in MSCs would abrogate their therapeutic efficacy, thereby establishing that apoptosis of MSCs is necessary for the immunomodulatory effects exerted by their infusion. Our data demonstrated that MSC apoptosis and subsequent efferocytosis are required for their full immunosuppressive effects in vivo, answering the long-standing question of how MSCs mediate therapeutic effects that persist beyond their survival.

Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies.

While cognitive decline is clearly underlined by synaptic and neuronal dysfunction, other players are emerging as critical elements in the equation of brain ageing. Inflammation seems to be one of those, with pro-inflammatory factors being associated with poor cognitive performance, pointing to immune cells as important regulators in this process. The immune system is drastically affected with ageing. While the adaptive immune response comprising B-cells and T-cells is diminished, the innate immune system (i.e., cells of the myeloid lineage) shows an increase in the pro-inflammatory state, also known as "inflammaging". This chronic low-inflammatory state is mainly driven by macrophages and pro-inflammatory cytokines.

Cellular metabolism has emerged as a key player in the regulation of immune function, starting already at the level of myeloid versus lymphoid lineage decision and greatly affecting cellular behaviour in the mature immune cells. Several recent studies have suggested that an altered cellular metabolism in aged macrophages might directly contribute to the pro-inflammatory signature. However, the detailed mechanisms initiating this increased inflammation with aging remain unclear.

In a recent publication, researchers have elucidated this cascade using an impressive set of in vitro and in vivo experiments in mice and in human myeloid cells. They found that aged myeloid cells have a decrease in cellular respiration and a decrease in glycolysis, suggesting that aged myeloid cells undergo a general bioenergetic failure. The proposed driving cause is the increased prostaglandin E2 (PGE2) signaling in the ageing myeloid compartment, mediated by the age-dependent upregulation of EP2, one of the four PGE2 receptors.

Conditional knockout of EP2, specifically in the myeloid cells of aged mice proves to be indeed an effective strategy at multiple levels. First, it rescues the expression of some of the immune factors upregulated with age, both in the plasma and in the hippocampus. Second, the loss of EP2 also reduces glycogen levels, normalizing the metabolic state and the associated mitochondrial defects observed in old macrophages. Surprisingly, restoring the PGE2 signaling in myeloid cells to a youthful state is enough to prevent age-dependent cognitive decline.

Overall, this data supports an upstream role of peripheral myeloid cells in orchestrating the process of brain ageing, underscoring the important cross-talk between the immune and the central nervous systems. This study nicely illustrates the importance of the cellular metabolic state of myeloid cells: it highlights that not only the availability of glucose, but also its channeling into different pathways (glycolysis versus glycogen synthesis) contributes to maintaining proper myeloid function.

Kugel's artery is defined as a rare anatomical variant of the coronary artery vascular bed consisting of an anastomotic connection between branches of the right coronary artery (RCA) and/or left circumflex artery (LCX). Kugel's artery has been reported to have an incidence of 6% in the general population. The presence of this anastomotic communication may play a pathophysiological role in a patient with a right dominant coronary circulation and an underlying coronary artery disease (CAD) affecting the right coronary system. There exist only a few reported cases of Kugel's artery with the pathophysiological relationship in CAD remaining unclear. Herein, we present a case with multivessel occlusion myocardial infarction found to have anomalous vascular anastomosis between the proximal RCA and distal segment of the same artery.

A 67-year-old African American male with no significant past medical history presented to the emergency room for an out-of-hospital witnessed cardiac arrest. In this case, the Kugel's artery was found to connect the proximal RCA to the branches of the distal RCA. The patient was found to have inferior anterolateral myocardial infarction on EKG and coronary angiogram revealed complete total occlusion of RCA and obtuse marginal. With total occlusion of the RCA one would expect to have a clinically significant myocardial infarction earlier in life, however, because of the patent Kugel's artery, the territory of RCA had viable blood supply and the presentation was most likely due to occlusion of the second obtuse marginal branch of the LCX. This bears out the observation by previous studies that collateral circulation was not seen in angiography until the degree of arterial occlusion is greater than 90%.

A favorable long-term prognosis is associated with good collateralization in patients with angiographically-proven single or double vessel CAD. Based on our patient's EKG and coronary angiogram findings, his acute presentation was most likely due to myocardial infarction in the LCX territory. He denied previous cardiorespiratory symptoms which may indicate myocardial viability in the distribution of RCA maintained by the Kugel's artery. Understanding the existence and significance of Kugel's artery and the anastomotic network cannot be overemphasized. The presence of an anomalous vascular connection bypassing an area of epicardial vessel occlusion may be a lifesaving pathophysiological finding that maintains myocardial perfusion and viability.

Long-term exposure to household air pollution (HAP) is a public health problem worldwide and is among the top 10 hazard factors for disease. Solid fuel is the largest source of HAP worldwide, where nearly a third of the population in low- and middle-income countries (LMICs) rely on it for primary domestic cooking, heating, or lighting energy. Notably, exposure to air pollution from solid fuel burning may directly or indirectly contribute to over 4 million deaths and 110 million disabilities annually.

The association of solid fuel use and common diseases has been proved in many studies on the elderly. Owing to physical limitations and social factors, the elderly are generally most active in and around the house, and they willingly perform housework and spend more time on it as they age. A cohort study indicated that the use of biomass fuel is associated with higher hazard ratios (HRs) of hypertension among the elderly (aged ≥65 years). The Chinese Longitudinal Healthy Longevity Survey (CLHLS) is an open, prospective, and national cohort of community-dwelling Chinese aged 65 years. In this study, we investigated whether the type of fuel used for cooking is associated with subsequent 8-year mortality and whether switching the fuel used for cooking for 4 years is associated with changes in HR with successive 5 years of follow-up.

Among the participants in the 2011-2018 survey, 53% reported using solid fuel. Such group was associated with a 9% increase in mortality risk relative to clean fuel users (HR = 1.09). Among participants in the 2014-2018 survey, 339 reported a switch from solid to clean fuels and they were not at increased mortality risk relative to the 488 people that reported a stable use of clean fuels (HR = 1.14) although the estimated HR was similar to the one for stable solid fuel users (HR = 1.19). Interaction and stratified analyses showed that solid fuel use had an impact on mortality in participants who were non-current smokers, had low dietary diversity scores, and were living in areas with high PM2.5 concentrations (over 50 μg/m3) and city population below 8 million. These findings showed a clear association between solid fuel use and mortality among older Chinese, and an even stronger association between risk of mortality and solid fuel use among individuals exposed to high levels of PM2.5.

Researchers have shown that cellular senescence, which occurs when aging cells stop dividing, is caused by irreversible damage to the genome rather than simply by telomere erosion. This discovery goes against the scientific model most widely adopted in the last 15 years, which is based on one principle: telomeres, caps located at the ends of chromosomes whose purpose is to protect genetic information, erode with each cell division. When they get too short, they tell the cell to stop dividing, thus preventing damage to its DNA. Made dormant, the cell enters senescence.

"What's most surprising is that, before really entering senescence, the cells divide one last time. In fact, the cell division caused by telomere dysfunction is so unstable that it ends up creating genetic defects. Contrary to what was believed, senescent cells have an abnormal genome. That's what we show in our study. Genetically, we were able to reproduce the phenomenon of cellular aging in the laboratory and ensured that all the telomeres of a population of cells became dysfunctional. With our equipment, we then observed in real time what was happening inside each single cell."

With time, senescent cells build up in the body and are responsible for the development of diseases such as cancer. This study, therefore, opens up new research opportunities. For example, could telomeres be repaired prior to the senescence phase, thereby preventing cellular aging and genomic instability? The scientific community has been debating this potential cellular rejuvenation for several years now. Nevertheless, these emerging therapeutic approaches still need fine-tuning.

A growing amount of evidence suggests that inflammation plays a critical role in the physiological aging process. Many studies have shown that the activated chronic inflammatory response is involved in aging-related diseases. Aging-related inflammation is characterized by increased levels of IL-6, IL-1β, TNF-α, and type I interferon. This chronic activation of the innate immune system in the absence of infection during the aging process is called inflammaging. The activated innate immune system in aging causes insulin resistance and oxidative processes, making the cardiovascular system more vulnerable to stress, thereby increasing the risk of cardiovascular diseases. Moreover, some studies have shown that inhibiting inflammation could reduce the occurrence of cardiovascular diseases in aging, suggesting the important role of inflammation in aging-induced cardiovascular injury.

The mechanism responsible for inflammaging is still far from clear. Metabolic disorders, mitochondrial dysfunction, DNA damage, and autophagy deficiency are all involved in inflammaging. The damaged DNA or self-derived molecules released from damaged cells are called damage-associated pattern molecules (DAMPs). Usually, DAMPs are transferred into lysosomes and then degraded. The accumulation of excessive DAMPs will lead to inflammation. TLR4 is an innate immune receptor that specializes in sensing DAMPs. When sensing DAMPs, TLR4 triggers intracellular signaling pathways which subsequently activate downstream inflammatory responses, leading to the release of inflammatory factors.

The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4-/- mice. In wild-type mice, TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders characterized by ineffective hematopoiesis resulting in peripheral blood cytopenias. MDS typically occur at an advanced age with a median age at diagnosis of 68 to 75 years. MDS as clonal disorders may be preceded by a state of clonal hematopoiesis (CHIP) in which MDS defining features cannot (yet) be substantiated. Whereas CHIP-specific somatic mutations are rarely detected in persons younger than 40 years, they reveal an increasing incidence with advanced age.

Considerable progress has been made in deciphering the biology of normal aging, which includes the distinction of normal aging from pathologies associated with aging; additional progress has been made in describing MDS preceding states and elucidating initiation and progression of this disease. Despite these data, the provocative question, if MDS is simply a variant of the aging process, remains challenging.

The earliest answers supporting this hypothesis come from epidemiologic data with a clearly increasing incidence of MDS with age. As always, this observed correlation needs to be supported by establishing a causal relationship. Some similarities between aging and MDS have undoubtedly been defined. Especially changes affecting hematopoiesis are suggestive for an involvement of aging in the development of a hematologic disorder. One example is aging hematopoiesis as a result of clonal selection of hematopoietic stem cells leading to an alteration of the HSC pool. Another is clonal hematopoiesis such as defined in CHIP which is recognized as a potential pre-MDS state with a continuous increase at an advanced age.

CHIP has not only implications for MDS but also for other conditions or diseases associated with aging such as cardiovascular disease which further supports the connection with aging. Finally, many of the biologic features that drive the MDS process can also be observed in processes of aging or are key players in non-hematologic diseases of the elderly. On the other hand, there are clear data demonstrating that MDS is not inevitable with aging: for example, the risk of developing hematologic malignancies, particularly MDS, is higher in patients with clonal hematopoiesis than in persons without, but by far not all of them develop MDS. In addition, as far as we know, not every person contracts MDS, if he or she gets just old enough.

A possible solution for this conundrum is the notion that aging certainly contributes to the development of MDS. One might hypothesize that in many cases aging is the main driver of MDS, whereas in others aging promotes the specific phenotype. MDS might thus be seen as an interplay of clonal disease and normal or premature aging. Probably different subtypes or disease entities of MDS are distinctively affected by aging.

NF-κB is an inducible transcription factor capable of regulating diverse biological processes, including inflammation, immunity, stress responses, cell proliferation, differentiation, and survival. A wide range of external, internal, and environmental inducers can activate the NF-κB signaling including growth factors, viral or pathogenic assaults, tissue injury, genotoxic, oxidative, and inflammatory stresses. Subsequent signaling cascades in most cases converge on the IKK complex formed by two catalytic subunits, IKKα and IKKβ, and a regulatory subunit IKKγ (NEMO). Activated IKK complex phosphorylates IκB proteins, leading to its subsequent degradation. As a result, the NF-κB dimer sequestered in the cytoplasm is liberated and translocated to the nucleus to activate specific transcriptional machinery.

Normal activation of NF-κB is required to maintain many physiological functions, whereas its abnormal or chronic activation have been linked to many inflammatory and age-related diseases. NF-κB also plays key roles in cellular senescence and the aging process. Chronic inflammation, a hallmark of aging, also induces cellular senescence and promotes tissue aging. Bioinformatics studies demonstrated that NF-κB is the transcription factor most associated with mammalian aging. Furthermore, constitutive NF-κB activation drives senescence and mammalian aging, conferring expression of senescence-associated secretory phenotype (SASP) factors including pro-inflammatory cytokines and chemokines.

Acute genetic blockade of NF-κB signaling in epidermis of old mice reduced the expression of age-associated genes and reverted many features of aging to that observed in young mice. We and others also demonstrated that inhibition of NF-κB by genetic depletion of one allele of the p65 subunit of NF-κB delayed the onset of aging-related symptoms and extended healthspan in progeroid mice.

Given its key role in senescence and aging, the NF-κB signaling pathway presents a therapeutic target for extending healthspan. Previously, we developed the small molecule SR12343 capable of inhibiting NF-κB activation by disrupting the association between IKKβ and NEMO. SR12343 was developed to act as a mimetic of the NEMO Binding Domain (NBD) peptide shown previously to improve pathology in many pre-clinical models as well as to reduce senescence and improve healthspan in a mouse model of accelerated aging. Treatment with SR12343 demonstrated positive effects in murine models of acute inflammation. Here, we examined the therapeutic potential of SR12343 in reducing cellular senescence and extending healthspan using both cell-based models and mouse models of accelerated and naturally aging.

SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity in oxidative stress-induced senescent mouse embryonic fibroblasts as well as in etoposide-induced senescent human IMR90 cells. Chronic administration of SR12343 to mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2-year-old wild-type mice. Taken together, these results demonstrate that the IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan, and treating age-related diseases.

UNITY Biotechnology, Inc. ("UNITY"), a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced 24-week data from its Phase 1 single ascending dose (SAD) safety study of UBX1325 in patients with advanced disease from diabetic macular edema (DME) or wet age-related macular degeneration (AMD). A majority of patients with DME across all doses had rapid improvements in vision, and patients in the higher dose cohorts showed a mean gain of 9.5 ETDRS letters in best-corrected visual acuity (BCVA) at 24 weeks following a single injection of UBX1325. Similarly, a majority of wet AMD patients treated with UBX1325 showed rapid gains in visual acuity, which were maintained through 12 weeks. In most patients, central subfield thickness (CST) remained stable through the study period.

The study enrolled a total of 19 patients with advanced DME (n=8) and wet AMD (n=11) for whom anti-VEGF therapy was no longer considered beneficial. UBX1325 was well-tolerated at all doses tested (through 10 mcg) with no dose-limiting toxicities and no reported incidence of inflammation. The Phase 1 data show rapid improvements in visual acuity as measured by BCVA in patients with DME, with the majority of patients demonstrating sustained responses through 24 weeks.

"A 10 letter gain in DME patients, maintained through six months, is an impressive outcome, and is particularly noteworthy considering that it was achieved with a single injection. Hard-to-treat patients require as many as 10 injections in the first year of treatment to see full benefits from currently available anti-VEGF therapies. A treatment that reduces the frequency of injections while showing meaningful and sustained improvements in BCVA would be of huge value for patients and physicians."

The human skin is inhabited by a large number and variety of microorganisms, including bacteria, fungi, and viruses. Although over- and underrepresented bacterial taxa can be readily associated with younger or older skin, the limiting step and challenge in the analysis of these data is the interpretation of biological relevance in context of the research question or hypothesis. Specifically, little insight is currently available in literature on the interplay between microbial functionalities and human cellular processes (referred to as co-metabolism).

To obtain more insight into the connection between the skin microbiome and the human physiological processes involved in skin aging, we performed a systematic study on interconnected pathways of human and bacterial metabolic processes that are known to play a role in skin aging. The bacterial genes in these pathways were subsequently used to create Hidden Markov Models (HMMs), which were applied to screen for presence of defined functionalities in both genomic and metagenomic datasets of skin-associated bacteria. These models were further applied on 16S rRNA gene sequencing data from skin microbiota samples derived from female volunteers of two different age groups: 25-28 years ('young') and 59-68 years ('old').

The results show that the main bacterial pathways associated with aging skin are those involved in the production of pigmentation intermediates, fatty acids, and ceramides. This study furthermore provides evidence for a relation between skin aging and bacterial enzymes involved in protein glycation. Taken together, the results and insights described in this paper provide new leads for intervening with bacterial processes that are associated with aging of human skin.

In a new study, researchers compare the genomes of nearly two-thirds of the known species of rockfish that inhabit coastal waters around the Pacific Ocean and uncover some of the genetic differences that underlie their widely varying lifespans. Some rockfish, like the colorful calico rockfish (Sebastes dallii), live for little more than a decade, while the most long-lived of the genus Sebastes - the rougheye rockfish (Sebastes aleutianus), which can be found from Japan to the Aleutian Islands - can hang out on the seabed in cold, deep coastal waters for more than 200 years.

Their wide range of lifespans, not to mention differences in size, lifestyle, and ecological niche evolved over a mere 10 million years - one of the most rapid radiations among all fishes. To uncover the genetic determinants of lifespan in rockfish, the researchers obtained tissue samples from 88 species and sequenced their complete genomes. The researchers looked for DNA variations that were more common in fish with longer lives and found 137 longevity-associated gene variations. Not all of these have a direct effect on lifespan, however. The researchers took care to separate out the genetic variations that allowed rockfish to adapt to deeper depths and grow to larger size, since those adaptations themselves have the side-effect of increasing lifespan. Deeper, cooler waters slow metabolism, for example, which is associated with a longer lifespan in many animals.

"We can explain 60% of the variation in lifespan just by looking at the size at maturity and the depth at which a fish lives. So, you can predict lifespan with pretty high accuracy just from these factors. This allowed us to identify the genes that allow them to do those things." The remainder of the longevity-associated variation primarily involved three types of genes: an enrichment in the number of genes for repairing DNA; variations in many genes that regulate insulin, which has long been known to influence lifespan; and an enrichment for genes that modulate the immune system. More DNA repair genes could help protect against cancer, while more immune genes could help ward off infections, as well as cancer.

Leaders from across the longevity sector came together in London today 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." Three of the LBA's founding members announced the launch at today's Investing in the Age of Longevity event at Longevity Week, including Juvenescence co-founder and chairman Jim Mellon, Cambrian Biopharma founder James Peyer, and Mehmood Khan, CEO of Hevolution Foundation.

On the academic side, LBA founding members include Harvard's David Sinclair, Nir Barzilai from the Albert Einstein College of Medicine, and Brian Kennedy from the National University of Singapore. In addition to Peyer, biotech company CEOs include BioAge's Kristen Fortney, Joe Betts-Lacroix of Retro Biosciences, and Matthias Steger of Rejuveron Life Sciences. Beyond Mellon and Kahn, investors are also represented by The Longevity Fund's Laura Deming, Nils Regge of Apollo Health Ventures, Michael Greve of the Forever Healthy Foundation, and Longevity Vision Fund's Sergey Young.

"I think the LBA will be a powerful and necessary force for the coming years… The ambition of the industry over the next 10 years is to completely upend the conception of aging that most people have… and the bottom line is, the industry has come of age." The LBA has several main objectives, the first of which is to "educate governments, the media, the public and the medical field about the promise of emerging therapies with the potential to treat or prevent multiple age-related conditions at once." Other goals include supporting newcomers to the industry and to help foster the creation of industrywide best practices.