Fight Aging! Newsletter, September 18th 2023

The mammalian brain is traditionally described as a network of neurons and glia, in which maturation and establishment of connectivity occur shortly after birth, followed by circuit refinement throughout the early part of life. Yet, there are exceptions concerning the timing of maturation because specific types of neurons are added progressively to the brain circuits during the adulthood. Some well-known neuronal "latecomers" are those originating from the brain areas designated as adult neurogenic niches.

Recent studies and new technology allowed researchers to update the current concepts of adult neurogenesis by revealing the existence of other types of neuronal precursors, which reside outside the neurogenic niches. Although generated during the embryonic development, these cell types retain post-mitotic immaturity until adulthood. During adulthood, such neuronal precursors, herewith referred to as "dormant precursors," eventually awaken and become adult-matured neurons (AM). Much about the awakening and maturation of dormant precursors is yet to be revealed. So far, several works in different mammalian species suggested that dormant precursors occupy numerous brain regions.

We previously demonstrated that, after awakening, dormant precursors undergo axonal sprouting, formation of synapses, and the progressive acquisition of functional input and output during the transition from precursor to AM. At the same time, we were puzzled to note that while many dormant precursors undertook the course of maturation during early adulthood, some cells remained immature throughout adulthood. Similar observation was also common in other mammalian species, including primates and humans.

Consequently, we questioned whether the precursors remaining dormant for most of a lifetime can actually eventually awake and follow a course of late maturation or whether they fail to awaken altogether. On the one hand, we speculated that the aging of the brain may hinder or completely impair the awakening. On the other hand, if late awakening and maturation were possible, this would imply that the old brain in mammalians is equipped with an unexplored source of young neurons.

The aging process is often accompanied by a decline in the proper functioning of the hematopoietic and immune systems, making older adults more susceptible to infections, blood disorders, and even tumor development. A new study focused on a key player in the blood system - hematopoietic stem cells (HSCs). These cells are responsible for generating various types of blood cells, playing a critical role in maintaining a healthy immune system. As we age, HSCs experience a decline in their ability to regenerate blood and show a preference for a specific type of cell lineage, which contributes to immune system dysfunction.

By introducing a natural compound called Urolithin A, which targets mitochondria - the energy powerhouses of cells - researchers were able to reverse the decline in HSC function. Mitochondria abnormalities were identified as a contributing factor to the aging of HSCs. Urolithin A acted as a mitochondrial modulator, effectively restoring the mitochondrial function within HSCs. Urolithins are not found in food; however, their precursors are. Urolithin A is the result of transformation of ellagic acids and ellagitannins by the gut microflora in humans.

The most interesting finding of this preclinical study was that this intervention not only rejuvenated the blood reconstitution capability of older HSCs but also improved immune system function in aged mice. When Urolithin A was incorporated as a dietary supplement, it not only revitalized the immune system's lymphoid compartments but also enhanced overall HSC performance. This translated to an improved immune response against viral infections, showcasing the potential of Urolithin A to combat age-related immune system decline.

Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs.

The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.

Senescent cells are old, sick cells that cannot properly repair themselves and don't die off when they should. Instead, they function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.

For the current study, the research team enrolled five participants aged 65 and older with symptoms of early-stage Alzheimer's disease. Participants received oral dasatinib plus quercetin over two consecutive days, followed by two weeks of no drugs. The cycle repeated six times for a total of 12 weeks. The research team also collected data on the safety and efficacy of the two drugs by monitoring side effects. They assessed biomarkers of senescence in cerebrospinal fluid (CSF) and blood, and also evaluated patients' cognition and brain images before treatment and after they completed the 12-week study. They found that both dasatinib and quercetin levels increased in the blood, and dasatinib was detected in the CSF in four subjects. Quercetin was not detected in the CSF of any participant. "We also determined that the treatment was safe, feasible and well-tolerated. There were no significant changes in brain function as determined by assessing memory and brain imaging to provide additional evidence that it is a safe therapy to evaluate further." Researchers also saw evidence to suggest that the combination therapy cleared amyloid from the brain and lowered inflammation in the blood. "However, we shouldn't over-interpret these results. There was a small number of people enrolled, there was no placebo arm to compare results."

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility, and efficacy. Five participants (mean age = 76 years) completed the 12-week pilot study.

D and Q levels in blood increased in all participants. In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile.

CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels. In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability, and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies.

Mitochondria are cellular organelles which generate adenosine triphosphate (ATP) molecules for the maintenance of cellular energy through oxidative phosphorylation. They also regulate a variety of cellular processes including apoptosis and metabolism. Of interest, the inner part of mitochondria - the mitochondrial matrix - contains a circular molecule of DNA (mtDNA) characterised by its own transcriptional machinery. As with nuclear DNA, mtDNA may also undergo nucleotide mutations that have been shown to be responsible for mitochondrial dysfunction.

During physiological aging, the mitochondrial membrane potential declines and associates with enhanced mitophagy to avoid the accumulation of damaged organelles. Moreover, if the dysfunctional mitochondria are not properly cleared, this could lead to cellular dysfunction and subsequent development of several comorbidities such as cardiovascular diseases (CVDs), diabetes, respiratory diseases, as well as inflammatory disorders and psychiatric diseases.

As reported for genomic DNA, mtDNA is also amenable to chemical modifications, namely DNA methylation. Changes in mtDNA methylation have shown to be associated with altered transcriptional programs and mitochondrial dysfunction during aging. In addition, other epigenetic signals have been observed in mitochondria, in particular the interaction between mtDNA methylation and non-coding RNAs. Mitoepigenetic modifications are also involved in the pathogenesis of CVDs where oxygen chain disruption, mitochondrial fission, and reactive oxygen species (ROS) formation alter cardiac energy metabolism leading to hypertrophy, hypertension, heart failure, and ischemia/reperfusion injury.

In the present review, we summarize current evidence on the growing importance of epigenetic changes as modulator of mitochondrial function in aging. A better understanding of the mitochondrial epigenetic landscape may pave the way for personalized therapies to prevent age-related diseases.

Among Metazoa, bivalves have the highest lifespan disparity, ranging from 1 to 500+ years, making them an exceptional testing ground to understand mechanisms underlying aging and the evolution of extended longevity. Nevertheless, comparative molecular evolution has been an overlooked approach in this instance. Here we leveraged transcriptomic resources spanning thirty bivalve species to unravel the signatures of convergent molecular evolution in four long-lived species: Margaritifera margaritifera, Elliptio complanata, Lampsilis siliquoidea, and Arctica islandica (the latter represents the longest-lived non-colonial metazoan known so far). We applied a comprehensive approach - which included inference of convergent dN/dS, convergent positive selection, and convergent amino acid substitution - with a strong focus on the reduction of false positives.

Genes with convergent evolution in long-lived bivalves show more physical and functional interactions to each other than expected, suggesting that they are biologically connected; this interaction network is enriched in genes for which a role in longevity has been experimentally supported in other species. This suggests that genes in the network are involved in extended longevity in bivalves and, consequently, that the mechanisms underlying extended longevity are - at least partially - shared across Metazoa. Although we believe that an integration of different genes and pathways is required for the extended longevity phenotype, we highlight the potential central roles of genes involved in cell proliferation control, translational machinery, and response to hypoxia, in lifespan extension.

Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process. However, there is emerging evidence that thymic involution is linked to T cell aging, chronic inflammation, and increased morbidity. Other factors, aside from chronological age, have been proposed to affect the involution rate. In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. The major aims were to establish the prevalence of fatty degeneration of thymus and to determine its associations with demographic, lifestyle, and clinical factors, as well as inflammation, T cell differentiation, and thymic output.

In total, 1,048 randomly invited individuals (aged 50-64 years, 49% females) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size and a 4-point scoring system, with scale 0-3 based on the ratio of fat and soft tissue. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation. Age, male sex, high BMI, abdominal obesity, and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8+ T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels.

Fasting is known to influence the immune functions of leukocytes primarily by regulating their mobilization and redistribution between the bone marrow and the peripheral tissues or circulation, in particular via relocalization of leukocytes back in the bone marrow. However, how the immune system responds to the increased risk of invasion by infectious pathogens with fewer leukocytes in the peripheral blood during fasting intervention remains an open question.

We used proteomic, biochemical and flow cytometric tools to evaluate the impact of short-term intensive fasting (STIF), known as beego, on red blood cells by profiling the cells from the STIF subjects before and after 6 days of fasting and 6 days of gradual refeeding. We found that STIF, by triggering the activation of the complement system via the complement receptor on the membrane of red blood cells, boosts fairly sustainable function of red blood cells in immune responses in close relation to various pathogens, including viruses, bacteria, and parasites, particularly with the pronounced capacity to defend against SARS-CoV-2, without compromising their oxygen delivery capacity and viability.

Aging of the hematopoietic system promotes various blood, immune, and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction. Autophagy is central for the benefits associated with activation of longevity signaling programs, and for HSC function and response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional. However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown.

Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche. We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement can preserve functional quiescence by enabling metabolic adaptation to glycolytic impairment.

Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.

Longevity biotech Rejuvenation Technologies has emerged from stealth with seed financing to develop mRNA-based therapeutics to address mechanisms of aging. The company says it has developed an mRNA approach "capable of rewinding 10 years of telomere shortening with a single dose." Rejuvenation's products are optimized telomerase mRNA encapsulated in a custom tissue targeted lipid nanoparticle. The company says it plans to expand its operations and bring on additional team members to oversee scale-up manufacturing, clinical operations, and R&D efforts to expand mRNA delivery capabilities to additional organ systems.

"A single dose of our telomerase mRNA reverses years of telomere shortening in hours. Rejuvenation's LNP technology can also deliver mRNA to the lung and liver, and we've shown remarkable efficacy in preclinical models in both liver fibrosis and liver failure."

The search for interventions to slow down and even reverse aging is a burgeoning field. The literature cites hundreds of supposedly beneficial pharmacological and genetic interventions in model organisms: mice, rats, flies and worms, where research into physiology is routinely accompanied by lifespan data. Naturally the negative results are more frequent, yet scientifically quite valuable if analyzed systematically. Yet, there is a strong "discovery bias", i.e. results of interventions which turn out not to be beneficial remain unpublished.

Theoretically, all lifespan data is ripe for re-analysis: we could contrast the molecular targets and pathways across studies and help focus the further search for interventions. Alas, the results of most longevity studies are difficult to compare. This is in part because there are no clear, universally accepted standards for conducting such experiments or even for reporting such data. The situation is worsened by the fact that the authors often do not describe experimental conditions completely. As a result, works on longevity make up a set of precedents, each of which might be interesting in its own right, yet incoherent and incomparable. Here we point out specific issues and propose solutions for quality control by checking both inter-study and intra-study consistency of lifespan data.

Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. We investigated these questions by exposing adult mice to mild CR (i.e., 20% restriction) for up to 12 months and applied in vivo and in vitro metabolic phenotyping of beta cell function followed by single cell multiomics and multi-modal high resolution microscopy pipelines (electron, light, mass spectrometry, and isotope microscopy) to investigate how CR modulates beta cell heterogeneity and longevity.

Gene regulatory network analysis links this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.

The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action.

The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patients at risk for these comorbidities.

Mild cognitive impairment (MCI) is characterized by an abnormal decline in mental and cognitive function compared with normal cognitive aging. It is an underlying condition of Alzheimer's disease (AD), an irreversible neurodegenerative disease. In recent years, neuroinflammation has been investigated as a new leading target that contributes to MCI progression into AD.

In the present study, we assessed a set of various serum and cerebrospinal fluid (CSF) biomarkers, including AD hallmarks and central nervous system and peripheral system inflammatory mediators, in a cohort of 30 healthy control, 45 non-impaired control, and 30 mild cognitively impaired patients. Our results confirmed specific activation of inflammatory processes in the brain of the MCI cohort. Additionally, the presence of systemic biomarkers in the CSF of the MCI population could give an indication of blood-brain barrier (BBB) permeability. Finally, IL-1β was upregulated in MCI serum and correlated with NLRP3 activation biomarkers.

AD has been described as a cascade of several biochemical mechanisms. First, the amyloid plaques start to accumulate abnormally in the brain, triggering an inflammatory response that will chronically exacerbate amyloid deposition and neurotoxicity. This will be followed by the production and hyperphosphorylation of tau proteins generating neurofibrillary tangles. All three mechanisms together are then responsible for altering neuronal transmission in the brain, which results in cognitive decline. Consequently, it is the combination of amyloids, inflammation, and tau proteins together that is responsible for cognitive impairment. As our patients have MCI based on cognitive tests and potentially early AD onset, the stage of the disease could correspond to the transition between amyloid aggregation and inflammatory response activation.

The Open Genes database was created to enhance and simplify the search for potential aging therapy targets. We collected data on 2402 genes associated with aging and developed convenient tools for searching and comparing gene features. A comprehensive description of genes has been provided, including lifespan-extending interventions, age-related changes, longevity associations, gene evolution, associations with diseases and hallmarks of aging, and functions of gene products.

For each experiment, we presented the necessary structured data for evaluating the experiment's quality and interpreting the study's findings. Our goal was to stay objective and precise while connecting a particular gene to human aging. We distinguished six types of studies and 12 criteria for adding genes to our database. Genes were classified according to the confidence level of the link between the gene and aging. All the data collected in a database are provided both by an API and a user interface. The database is publicly available on a website at https://open-genes.org/.