Fight Aging! Newsletter, September 9th 2024

Hevolution Foundation has joined forces with Dolby Family Ventures to invest in Vandria, a company pioneering mitochondrial therapeutics, with a view to expediting the development of a promising drug designed to improve cognitive function. The total Series A financing now stands at 30.7 million, with Hevolution and Dolby Family Ventures joining ND Capital as institutional backers. This funding is set to facilitate the clinical advancement of Vandria's lead compound, VNA-318, a small molecule mitophagy inducer aimed at treating neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other age-related conditions.

The investment speaks to a growing interest in mitophagy - an essential cellular process that involves the selective removal and recycling of damaged mitochondria. Mitochondria are critical for maintaining cellular health, and their dysfunction is increasingly linked to numerous human pathologies, including neurodegenerative diseases, cardiovascular disorders, and cancers.

"This financing will enable us to progress further in clinical development with runway from the Series A to complete the Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) first-in-man Phase 1 study of VNA-318 and to initiate three parallel Phase 1b/2a efficacy studies in 2025, subject to positive progress in the Phase 1 and regulatory approvals."

Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. The maximum known life extension of mice, resulting from a single intervention, does not exceed 50% (Snell mice with Pit1 knockout or Ames mice with Prop1 knockout). Even in these cases the lifespan of mice is much lower than that of similarly sized mammals with negligible senescence such as the naked mole-rat Heterocephalus glaber, indicating that none of these interventions was sufficient to stop aging. One possible explanation is that even if one underlying cause of aging is countered, the remaining aging processes will still limit the animal's lifespan. Thus, we propose the hypothesis that combination therapies can be more efficient against aging.

Targeting multiple pathways at once can provide synergistic effects that are expected to be greater than the simple sum of independent effects. For example, chemotherapy kills cancer cells leading to proliferation of cancer-targeting T cells. However, some cancers evolve adaptations that suppress this immune response. Checkpoint inhibitors can lift this suppression allowing T cells to be more effective. Several clinical trials have revealed that chemotherapy works better when combined with this form of immunotherapy. Similar examples can be found in the field of aging research. Using the model organism C. elegans researchers have shown that a ribosomal protein S6 kinase beta deletion allele, daf-2 loss-of-function allele and their combined effects increase the worm's lifespan by 20%, 168.8% and 454.4% respectively. A combination of trametinib, rapamycin, and lithium increase the longevity of Drosophila more than each single intervention or pairs of interventions. These drugs inhibit mitogen-activated protein kinase kinase, mTOR complex 1, and glycogen synthase kinase-3 respectively, thus targeting various components of the nutrient-sensing network. Generally, as aging-related pathologies are typically comorbid, targeting multiple biological processes or their separated nodes may be more effective than targeting a single one.

Currently, the most comprehensive analysis of synergistic anti-aging interactions is provided by the SynergyAge database which contains the current state of the art collection of data on long-lived and short-lived genetic mutants with over 1800 gene combinations. However, the database does not cover pharmacological and gene therapy interventions which are arguably more relevant for practical human lifespan extending application. Here we review existing data on combinations of pharmacological and genetic interventions targeting one or many pathological processes described as the hallmarks of aging in mice. While we also discuss studies performed on other mammals, we focus on mice because they were used in the largest number of longevity intervention studies. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.

Heterochronic parabiosis has proven to be a valuable tool to decipher some key circulating molecules involved in the aging process, both promoting and delaying it. In general, circulating factors exchanged during parabiosis may promote or delay cellular senescence and help eliminate senescent cells. Parabiosis also appears to rejuvenate mitochondrial function in several contexts. Parabiosis has also been shown to regulate inflammatory processes, either by promoting them during accelerated aging or by preventing them during induced rejuvenation. Specifically, in the brain, accelerated aging leads to altered intercellular communication and increased DNA damage culminating in genetic instability. In contrast, induced rejuvenation enhances proteostasis and epigenetic modifications. In bone marrow, muscle and liver, stem cell depletion is mitigated during induced rejuvenation. Mitochondrial function is improved in brain, hematopoietic and immune cells, vascular endothelium, and muscle. In addition, macroautophagy plays a crucial role in muscle and kidney rejuvenation. Accumulation of senescent cells in the brain, pancreas, hematopoietic and immune cells, muscle, and VAT is prevented during induced rejuvenation. Chronic inflammation is favored during accelerated aging by parabiosis in the brain, bones, muscles, liver, vascular endothelium, kidneys, eyes, and VAT. In contrast, induced rejuvenation reduces inflammation in these tissues and organs.

Proteins identified as relevant in the aging process through this strategy are poised to be prominent targets, first to better understand this intricate process and then to elucidate strategies to delay the harmful effects of aging, such as various age-related diseases, thus improving our quality of life. Researchers around the world can search for inhibitors for targets that promote aging and activators for those that delay it.

It is important to note that one of the main challenges faced by studies on heterochronic parabiosis is that, in most cases, the conditions used vary significantly. This includes variations in factors such as the sex and age of the animals, their location and cross-linked blood vessels, the length of the cross-linking period, surgical procedures, diet, and exercise capacity, among other variables. Therefore, it would be appropriate to establish a convention where the conditions are the same or as similar as possible in order to enhance reproducibility.

Comparing the benefits of induced rejuvenation with the deleterious effects of accelerated aging is complex, as the changes do not usually occur in opposite directions within the same processes. On the contrary, they often involve changes in the same direction, possibly indicating repair, compensatory mechanisms, or alterations in entirely different processes. Despite this complexity, it would be valuable to find a method to evaluate these effects, possibly using statistical and computational models. Additionally, studies aimed at determining whether the age difference between animals and the duration of their cross-linking lead to significant variations in heterochronic parabiosis outcomes would be particularly insightful.

Also, it should also be noted that most studies focus mainly on circulating proteins, while information on other circulating biomolecules such as DNA, non-coding RNAs, extracellular vesicles, lipids, carbohydrates, and their metabolites is rather limited. Similarly, most research only considers blood cells, despite the fact that other cell types can be transferred. This disparity underscores the need for further research to better understand the roles and mechanisms of these less studied biomolecules and cells in various biological processes.

Exploring the combined dataset of transcriptomic, epigenomic, proteomic, and metabolomic information derived from various tissues and cells in parabiosis experiments has the potential to provide a holistic understanding of the aging process. This integrated approach could unveil intricate molecular mechanisms underlying aging-related changes, providing a comprehensive and structured view of how different biological pathways interact and contribute to aging. However, the analysis of these multidimensional data sets presents significant challenges due to their complexity and the large amount of information they encompass. This complexity is due to the interaction of various molecular processes and the need to integrate data from different omics levels.

There are still many challenges and opportunities to be explored with heterochronic parabiosis. Among them, standardizing protocols to obtain as much information as possible and ensure reproducibility, identifying more specific factors with pharmaceutical potential, defining how transferable the findings are to humans, among many other things. It would be interesting if similar experiments could be carried out in long-lived rodents, such as naked mole rats or blind mole rats, as well as in other mammalian models of aging, such as bats, or in animals that experience a rapid decline in health leading to death, such as boreal quolls during the breeding season. These studies could provide valuable information, especially when compared to findings in mice.

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy.

Long-standing frameworks that ageing is caused by a passive accumulation of molecular damage have been challenged in recent years. The emergence of proposed ageing hallmarks motivated substantial scientific efforts to combat these myriad of molecular perturbations, however, yielding limited success. Understanding if the proposed hallmarks of ageing are causally involved in the physiological decline of organisms, or if they represent mere secondary symptomologies to ageing deterioration, remains an ongoing effort. Indeed, considerable model organism research suggests these traits to be poor predictors of healthy ageing. Thus, whilst features of molecular damage, oxidative stress, and mitochondrial dysfunction are sure to plays important roles in exacerbating healthspan decline, proximate molecular events that underpin the onset of healthspan decline remain largely elusive and difficult to study. Evolutionary theory has long maintained that declines in the force of natural selection after sexual maturity allow the sub-optimal expression and function of fitness-promoting genes in late-life. Thus, genomes have evolved for developmental and reproductive success, not healthy ageing.

This suggests that evolutionary neglect encompasses the proximate cause of ageing onset, yet is unable to elucidate precisely which late-acting (pleiotropic) genes contribute to physiological decline. Identifying the entirety of late-acting hyperfunctional genes will, therefore, allow thorough investigations into optimising their expression levels at the organismal and tissue-specific level at geriatric life stages. We propose that combinations of untargeted multi-omics and late-life healthspan screening of gene-by-gene inhibition is the preferred strategy for studying the roles of hyperfunction in normal physiological ageing.

Bone marrow stromal/stem cells (BMSCs) are generally considered as the common progenitors for both osteoblasts and adipocytes in bone marrow, and have been shown to have great potential for clinical application. However, their number and function decline with aging, especially the preferential differentiation of aged BMSCs into adipocytes rather than osteoblasts is reasonably accepted as a leading cause of senile osteoporosis (SOP), which is characterized by increased bone marrow fat accumulation and decreased bone loss. Thus, the balance between osteogenic and adipogenic lineage commitment of BMSCs is essential for bone homeostasis.

Despite the fact that the mechanisms under which the lineage shift occurs in aged BMSCs are not fully clear, accumulated studies have showed that diversity strategies for BMSCs rejuvenation are of benefits for bone quality and even healthspan improvement. For example, modification of transcription factors, epigenetics, and autophagy that enhanced osteogenesis and decreased adipogenesis of BMSCs alleviated SOP in mice. The latest evidence uncovered that premature aging of skeletal stem/progenitor cells caused bone loss. Therefore, it is assumed that stimulation of bone formation by BMSCs rejuvenation in vivo is an effective and attractive strategy for age-associated bone loss.

Transcription factor EB (TFEB) is a key transcriptional regulator of autophagy and lysosomal biogenesis. Emerging discoveries demonstrated that TFEB overexpression promoted longevity and reduced the burden of diseases, holding great promise as a therapeutic strategy for multiple age-associated diseases. Regulation of TFEB has been shown to control the activities of osteoblasts and osteoclasts, the two main cells playing in the coupling of bone remodeling for homeostasis, implying its potential use in osteoporosis prevention. However, little is known about the relationship between TFEB activities and osteoporosis. As precursors of bone lineage cells, BMSCs directly contribute to bone remodeling by differentiating into osteoblasts, but how and to what extend TFEB regulates fate decision of aged BMSCs in bone marrow is still unclear.

In this study, we synthesized a novel small molecule compound (named "CXM102") that could promote autophagy activities in aged BMSCs via enhancement of TFEB nuclear translocation, leading to senescence rejuvenation and bone anabolic effects in middle age mice. Additionally, low dose and long-term administration of CXM102 showed better benefits for healthspan than rapamycin in mice, including extended lifespan, reduced serum levels of inflammation, less lipid droplets and fibrosis in organs. Our results demonstrated that CXM102 could significantly counteract aberrant lineage allocations of aged BMSCs, alleviate osteoporotic bone loss, increase healthspan and longevity of middle age mice.

CD4+T cells play a notable role in immune protection at different stages of life. As individuals age, significant alterations occur in the internal and external milieu of CD4+T cells. These changes encompass reduced naive CD4+T cell (CD4+TN) levels, thymic hypofunction, peripheral mechanism regulation, untimely quiescent withdrawal, and persistent environmental antigen stimulation. The interplay between the in vivo microenvironment and the aging immune system is intricately linked, resulting in a decline in effector CD4+ T cell (CD4+Teff) proliferation capacity, alterations in differentiation patterns, imbalances in the ratio of type 1 T helper cell (Th1) to type 2 T helper cell (Th2), changes in the ratio of type 17 T helper cells (Th17) to regulatory T cells (Treg), among others. Repeated antigenic stimulation, accelerated homeostasis, and delayed clearance lead to impaired mitochondrial respiration, reduced functionality, accumulation of memory subpopulations with autophagy deficits, loss of CD27 and CD28 surface molecule expression, increased production of cytotoxic molecules, and elevated levels of terminally differentiated CD4+T cells (CD4+TEMRA).

Enhancing the function of CD4+T cell phenotype and targeted depletion thereof represents a crucial approach for improving the immune microenvironment in elderly individuals. Future exploration can focus on the mitochondrial dysfunction, metabolic reprogramming, genetic and epigenetic changes, protein homeostasis imbalance, autophagy defects, loss of cellular plasticity, and reduction of T cell receptor (TCR) pool in aging CD4+T cells to clarify the nature of changes in different subtypes of CD4+T cells under immune aging. More attention should be paid to mutual influence and interaction in the process of CD4+T cell aging, which are necessary to reverse both multi-organ senescence and immune senescence. It is evident that CD4+T cells serve as the central hub, not only influencing other immune cell populations but also orchestrating changes within internal subsets and related signaling pathways.

The present study demonstrates that the expression of both cardiac contractile and regulatory proteins is altered during aging, and these changes contribute to the contractile deficits that are associated with aging. Our data show that during aging there is a significant increase in the expression of cardiac myosin heavy chain β (β-MyHC) and phosphorylation of both troponin I (TnI) and myosin-binding protein C (MyBP-C). Similar to our results, others have demonstrated an increase in cardiac β-MyHC during aging.

Cardiac myosin heavy chain α (α-MyHC) has been demonstrated to have a ~2-3 fold higher actin-activated ATPase and velocity of actin movement in the motility assay than cardiac β-MyHC. Additionally, in large mammals, cardiac α-MyHC produces an ~2x higher force compared to cardiac β-MyHC, while there is no difference in force for α-MyHC and β-MyHC in smaller mammals including the mouse and rat. Thus, the increase in the expression of β-MyHC in cardiac muscle during aging documented in the present study would be expected to result in a reduction in rate constant of force redevelopment after quick release and restretch (Ktr) and a decrease the rates of sarcomere length (SL) shortening and relaxation of single cardiomyocytes.

Aging is also well known to be associated with an increase in myocyte size and cardiac fibrosis, which is consistent with our results. Further, despite the increase in myocyte size, total MyHC expression did not change, and thus, the number of myosin filaments per myocyte cross-section would decrease and coupled with the increase in cardiac fibrosis would be expected to contribute to the decrease in the maximally Ca2+ activated force/cross-section in 24 months old rats.

In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is rare. This is unfortunate as aging induces many changes in the heart. As the heart ages, the capacity of the organ to respond to increased workload decreases. The stress this entails promotes diastolic dysfunction, arrhythmias, and heart failure. These changes to the normal function of the heart ensure that young and aged adults respond differently to cardiac injury.

In young adults, cardiac injury initially induces an inflammatory response whereby neutrophils, M1 macrophages, T-cells, and B-cells invade the injury area to remove dead cells and initiate the reparative phase. The reparative phase is associated with a shift in immune cell populations which actively resolve inflammation and induce fibroblasts to secrete fibrous tissue proteins. The latter results in a stable scar. In contrast, the inflammatory response in older hearts following injury is muted; resulting in delayed clearance of dead cells. Moreover, fibroblast responses to fibrotic cues are markedly weaker. Fibrous protein production is dampened, leading to weaker and less stable scars. Weaker scars affect cardiac function by increasing systolic dysfunction and dilative remodeling. Dampened immune and fibroblast responses in aged individuals lowers the capacity to respond to stressors.

Zebrafish spontaneously regenerate their retinas in response to damage through the action of Müller glia (MG). Even though MG are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration, with temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging but are still metabolically active, releasing a variety of signaling molecules as part of the senescence-associated secretory phenotype.

Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia /macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.

Human lifespan is shaped by both genetic and environmental exposures and their interaction. To enable precision health, it is essential to understand how genetic variants contribute to earlier death or prolonged survival. In this study, we tested the association of common genetic variants and the burden of rare non-synonymous variants in a survival analysis, using age-at-death (N = 35,551, median age-at-death = 72.4), and last-known-age (N = 358,282, median last-known-age = 71.9), in European ancestry participants of the UK Biobank.

The associations we identified seemed predominantly driven by cancer, likely due to the age range of the cohort. Common variant analysis highlighted three longevity-associated loci: APOE, ZSCAN23, and MUC5B. We identified six genes whose burden of loss-of-function variants is significantly associated with reduced lifespan: TET2, ATM, BRCA2, CKMT1B, BRCA1, and ASXL1. Additionally, in eight genes, the burden of pathogenic missense variants was associated with reduced lifespan: DNMT3A, SF3B1, CHL1, TET2, PTEN, SOX21, TP53, and SRSF2. Most of these genes have previously been linked to oncogenic-related pathways and some are linked to and are known to harbor somatic variants that predispose to clonal hematopoiesis. A direction-agnostic approach additionally identified significant associations with C1orf52, TERT, IDH2, and RLIM, highlighting a link between telomerase function and longevity as well as identifying additional oncogenic genes.

Our results emphasize the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.

The endoplasmic reticulum (ER) comprises an array of structurally distinct subdomains, each with characteristic functions. While altered ER-associated processes are linked to age-onset pathogenesis, whether shifts in ER morphology underlie these functional changes is unclear. We report that ER remodeling is a conserved feature of the aging process in models ranging from yeast to C. elegans and mammals. Focusing on C. elegans as an exemplar of metazoan aging, we find that as animals age, ER mass declines in virtually all tissues and ER morphology shifts from rough sheets to tubular ER. The accompanying large-scale shifts in proteomic composition correspond to the ER turning from protein synthesis to lipid metabolism.

To drive this substantial remodeling, ER-phagy is activated early in adulthood, promoting turnover of rough ER in response to rises in luminal protein-folding burden and reduced global protein synthesis. Surprisingly, ER remodeling is a pro-active and protective response during aging, as ER-phagy impairment limits lifespan in yeast and diverse lifespan-extending paradigms promote profound remodeling of ER morphology even in young animals. Altogether our results reveal ER-phagy and ER morphological dynamics as pronounced, underappreciated mechanisms of both normal aging and enhanced longevity.

Though previous studies of brain samples from Alzheimer's patients have provided insights into molecules involved in the disease, they have not revealed many details about where in the long sequence of events leading to Alzheimer's those genes play a role and which cells are involved at each step of the process. A new analysis required over 400 brains. Within each brain, the researchers collected several thousand cells from a brain region impacted by Alzheimer's and aging. Every cell was then run through single-cell RNA sequencing that gave a readout of the cell's activity and which of its genes were active.

Based on the data, researchers propose that two different types of microglial cells - the immune cells of the brain - begin the process of amyloid and tau accumulation that define Alzheimer's disease. Then after the pathology has accumulated, different cells called astrocytes play a key role in altering electrical connectivity in the brain that leads to cognitive impairment. The cells communicate with each other and bring in additional cell types that lead to a profound disruption in the way the human brain functions.

Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve.

Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activity-dependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important.

In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity.

Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion.

Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.

Among the 117,763 postmenopausal women in the UK Biobank (mean [SD] age, 60.2 [5.4] years), 47,461 (40.3%) had ever used hormone therapy (HT). The mean (SD) phenotypic age of the whole population was 52.1 (7.9) years. Individuals who had ever used HT were older in chronological and phenotypic age and less educated, and they had a lower income, higher exposure to nicotine, more prevalent chronic diseases, and higher proportions of bilateral oophorectomy and hysterectomy than those who never used HT.

In our study, using HT for 4 to 8 years was associated with 0.25 fewer years of biological aging discrepancy. In a previous study, middle-aged adults with 1 major chronic disease were an average of 0.2 years older in phenotypic age than disease-free counterparts. Moreover, each 1-year increment in phenotypic age (adjusted for chronological age) was associated with as much as a 9% higher all-cause and a 20% higher cause-specific mortality risk. Accordingly, the 0.25 years of delayed aging observed in our study could translate to approximately 2.25% decreased risk of all-cause mortality and 5% decreased risk of cause-specific mortality. Therefore, the observed magnitude of associations in our study could be relevant for current clinical practice.

In conclusion, postmenopausal women with historical HT use were biologically younger than those not receiving HT, with a more evident association observed in those with low SES. The biological aging discrepancy mediated the association between HT and decreased mortality. Promoting HT in postmenopausal women could be important for healthy aging.