Fight Aging!

The growing costs of obesity have prompted considerable research and development efforts focused on pharmacological approaches to weight loss. Another possible avenue is to develop drugs to reduce some of the negative impacts of aged and excess fat tissue, such as the chronic inflammatory signaling produced by visceral fat. While it is reasonable to argue that weight loss is the preferential approach for people who are overweight, comprehensive rejuvenation is not yet a reality and older people, even thin older people, undergo poorly understood and incompletely mapped changes in cell biochemistry and immune function that make fat tissue more inflammatory.

Inflammation in fat tissue is a function of the immune system, provoked by the metabolic activity of fat cells. Chronic, unresolved inflammation is harmful to tissue function throughout the body, contributing to the onset and progress of age-related disease. In today's open access paper, researchers discuss a potential regulator of this inflammation. They show that inhibiting the interaction between innate immune cell receptor BLT1 and its binding ligand LTB4 reduces both obesity-related and age-related inflammatory immune cell behavior in fat tissue.

Role for BLT1 in regulating inflammation within adipose tissue immune cells of aged mice

Aging is a complex biological process characterized by obesity and immunosenescence throughout the organism. Immunosenescence involves a decline in immune function and the increase in chronic-low grade inflammation, called inflammaging. Adipose tissue expansion, particularly that of visceral adipose tissue (VAT), is associated with an increase in pro-inflammatory macrophages that play an important role in modulating immune responses and producing inflammatory cytokines. The leukotriene B4 receptor 1 (BLT1) is a regulator of obesity-induced inflammation. Its ligand, LTB4, acts as a chemoattractant for immune cells and induces inflammation. Studies have shown that BLT1 is crucial for cytokine production during lipopolysaccharide (LPS) endotoxemia challenge in younger organisms. However, the expression patterns and function of BLT1 in older organisms remains unknown.

In this study, we investigated BLT1 expression in immune cell subsets within the VAT of aged male and female mice. Moreover, we examined how antagonizing BLT1 signaling could alter the inflammatory response to LPS in aged mice. Our results demonstrate that aged mice exhibit increased adiposity and inflammation, characterized by elevated frequencies of B cells and T cells, along with pro-inflammatory macrophages in VAT. BLT1 expression is the highest in VAT macrophages. LPS and LTB4 treatment result in increased BLT1 in young and aged bone marrow-derived macrophages (BMDMs). However, LTB4 treatment resulted in amplified Il6 from aged, but not young BMDMs. Treatment of aged mice with the BLT1 antagonist, U75302, followed by LPS-induced endotoxemia resulted in an increase in anti-inflammatory macrophages, reduced phosphorylated NFκB and reduced Il6.

In conclusion, this study provides valuable insights into the age- and sex- specific changes in BLT1 expression on immune cell subsets within VAT. This study offers support for the potential of BLT1 in modulating inflammation in aging.

An increase in hydrogen sulfide in tissues has been shown to modestly slow aging in mice, acting on some of the well-studied beneficial pathways and cellular maintenance mechanisms triggered by mild stresses. Here, researchers show that hydrogen sulfide upregulates autophagy in muscle tissue, making it one of many interventions that slow aging via this mechanism. The practice of calorie restriction appears to extend life in short-lived laboratory species largely via improved autophagy, but calorie restriction does not radically extend life in long-lived mammals. Calorie restricted mice may exhibit as much as a 40% longer life span, but calorie restricted humans certainly do not. As a result, researchers do not expect that any other autophagy-based approach will do much to extend human life span.

As individuals age, there is a concomitant decline in the number of muscle fibres and the cross-sectional area of muscle. The decline in mass and function of skeletal muscle in older adults often results in falls, disability and even death. Hydrogen sulfide (H2S) is a gasotransmitter that is produced endogenously in mammals, primarily through enzymatic pathways. H2S directly reacts with oxygen, hydrogen peroxide, and peroxynitrite, thereby reducing cellular oxidative damage. Additionally, it can modify proteins post-translationally through S-sulfhydration, which affects their functionality. Studies have demonstrated that human skeletal muscle expresses a considerable number of H2S-producing enzymes.

H2S has been shown to effectively alleviate muscle atrophy caused by diabetes and obesity. The precise mechanism by which this occurs is not yet fully understood. However, scientists have postulated that it may be related to H2S antioxidant stress, the regulation of mitochondrial energy metabolism, the reduction of apoptosis, and the up-regulation of autophagy. The objective of this study was to investigate whether H2S can enhance the expression and S-sulfhydration of USP5, thereby facilitating the deubiquitination of AMPKα1. Which, in turn, would result in the up-regulation of autophagy, which would contribute to the alleviation of skeletal muscle ageing. We find this to be the case.

Link: https://doi.org/10.1002/jcsm.13560

Taurine is a dietary amino acid. Circulating levels in the bloodstream decline with age, but can be restored by supplementation. Taurine supplementation has been shown to produce improved health and modest life extension in mice, and may act to improve protective cellular antioxidant mechanisms, though other mechanisms are likely involved. Human trials have been less promising, but largely predated modern approaches to measuring biological age, and may have been looking at overly specific measurable biomarkers of oxidative metabolism. Given that taurine is safe and cheap, it is an interesting intervention for self-experimenters, even though we shouldn't expect the effects on health and life span to be large in humans.

Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of the somatosensory barrel cortex, relying on the proper functioning and extensive up regulation of the GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice.

The present research explores two potential interventions, taurine supplementation, and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging. Still, they allow for increased somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.

Link: https://doi.org/10.1038/s41598-024-70261-5

Autophagy is the name given to the collection of processes that recycle damaged and excess proteins and structures in the cell. It encompasses mechanisms by which these recycling targets are first identified, then flagged, and finally transported to a lysosome where they are broken down. Upregulation of autophagy has been demonstrated to improve health and slow aging in a range of laboratory species, using a range of different strategies. Mild stress such as that provided by calorie restriction is known to upregulate autophagy, and many of the approaches discovered to date mimic some aspect of the calorie restriction response. Administration of rapamycin, for example, inhibits mTOR signaling to manipulate nutrient sensing in a favorable way.

In today's open access paper, researchers show that targeted upregulation of autophagy in bone marrow progenitor cell populations in aged mice can improve health very broadly, including reductions in inflammation. The actual intent was to slow the loss of bone mineral density that occurs with age, and the intervention achieves this goal as well. Further, the mice lived longer, but when this outcome occurs as a result of manipulating stress response mechanisms there is good reason to think that the degree of extended life in humans will be much smaller than that demonstrated in mice. Plasticity of longevity in response to low calorie intake is an adaptation to reduce the impact of seasonal famine, so only short-lived species exhibit relatively large changes in life span.

Rejuvenation of BMSCs senescence by pharmacological enhancement of TFEB-mediated autophagy alleviates aged-related bone loss and extends lifespan in middle aged mice

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.

Phenotypic age is a popular measure of biological age, in part because it is easily calculated using a few commonly available assays conducted on a blood sample. One of the interesting items in this study is the fact that average phenotypic age is somewhat lower than chronological age in a large population of older women. The other is that hormone replacement therapy has only a small effect on phenotypic age. As is the case for all current assessments of biological age, the actual utility of phenotypic age for an individual remains to be determined. Is it actionable, will it accurately reflect the effects of a particular intervention on future life expectancy? These questions do not have satisfactory answers at present.

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.

Link: https://doi.org/10.1001/jamanetworkopen.2024.30839

Reduced expression of SK61 is one downstream consequence of mTOR inhibition, a class of intervention that is demonstrated to slow aging in animal models. Researchers here down that SK61 inhibition reduces liver inflammation, in part by reducing the burden of senescent cells and their pro-inflammatory secretions. This in turn may be an important mechanism by which mTOR inhibition improves late life health.

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.

Link: https://doi.org/10.1038/s43587-024-00695-z

Hyperfunction theories of aging have emerged in recent years from the programmed aging camp, vary considerably, and have yet to settle down into a single consensus hyperfunction theory. Roughly speaking, in this viewpoint aging is the consequence of the inappropriate continued activity or reactivation of developmental programs in adult life. This view of aging does not necessarily stand in opposition to the consensus antagonistic pleiotropy viewpoint, in which aging is the consequence of unrepaired damage that accumulates because selection pressure is too weak in late life for better repair systems to emerge. In some cases hyperfunction is seen as a part of this damage. In others, hyperfunction is seen as the underlying cause of aging, a program, while damage is a secondary consequence.

Today's example of hyperfunction theorizing is one of those that downplays the view of accumulated damage, painting damage as a secondary consequence of the underlying program of aging. The authors makes some practical suggestions regarding the way in which research should progress if hyperfunction is the driving theory: find overactivated and harmful development-associated genes and suppress their activity. Theory drives research strategy, and this is why battles over theories of aging are important. If the wrong approach to theory wins out, research and development will tend to lead to only poorly effective therapies, because those therapies fail to address causes of aging and are instead targeting side-effects of aging.

Consolidating multiple evolutionary theories of ageing suggests a need for new approaches to study genetic contributions to ageing decline

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.

The brain continually adjusts the networks of synaptic connections between neurons, and cognitive functions such as memory and learning absolutely require this ongoing plasticity of neural networks. With aging synaptic plasticity declines, and this loss of function is an important component of cognitive decline and the development of neurodegenerative conditions. Finding ways to improve this plasticity in an aged brain, and to a greater degree than can be achieved by exercise, is a necessary component of research into the treatment of aging.

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.

Link: https://doi.org/10.3389/fnagi.2024.1428244

A better understanding of how exactly Alzheimer's disease progresses may open the door to more effective early intervention aimed at preventing the condition from occurring. The study noted here adds to the evidence for inflammatory dysfunction of microglia as an important early stage in Alzheimer's disease. A broad range of approaches under development can adjust the behavior of microglia, destroy senescent microglia, or even clear all microglia. The animal data supports efforts to test these approaches in Alzheimer's patients, and particularly in the earliest stages of the condition, prior to symptoms, now that assays exist to detect pre-symptomatic Alzheimer's disease.

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.

Link: https://www.cuimc.columbia.edu/news/cellular-community-brain-drives-alzheimers-disease

In heterochronic parabiosis, the circulatory systems of an old mouse and young mouse are surgically joined. It is now well established that this accelerates measures of aging in the young mouse, and reverses measures of aging in the old mouse. This observation has given rise to a rapidly shifting area of research that has evolved in a number of directions over the past twenty years. Competing hypotheses regarding the mechanisms by which sharing blood in this way can impact aging have fallen in and out of favor, but are largely still present in some form - and still competing.

Initially, the focus was on factors present to a larger degree in young blood that may encourage favorable changes in the behavior of aged cells and tissues. GDF-11 was an initial discovery, and remains under clinical development as a mode of therapy. Other factors identified as potentially beneficial include oxytocin. Early approaches to build therapies based on transfusion of plasma from young individuals into old individuals produced poor results in both animal studies and human clinical trials, however.

Over time, the view shifted to harmful factors present to a larger degree in aged blood. Dilution of those factors was seen as the critical point, giving rise to experiments in which diluting blood with saline and albumin in aged individuals appeared to produce benefits in animal studies. Human clinical trials remain a work in progress, and it is yet to be settled as to how useful this approach to therapy will turn out to be - not to mention optimal treatment protocols and duration of benefits from a single treatment. At the end of the day, while clinical applications are under development, it remains to be settled as to exactly why heterochronic parabiosis works to improve function in the older mouse. Which mechanisms are valid, and what is the relative importance of those mechanisms? Research moves slowly.

Aging insights from heterochronic parabiosis models

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.

The endoplasmic reticulum is a cell structure associated with ribosomes that aids in protein folding and protein transport, but also has a range of other purposes. It is an important component of the machinery that builds proteins and other molecules in the cell. Like other organelles, the endoplasmic reticulum is subject to the cell maintenance processes of autophagy, in which structures or their component parts are identified as worn, damaged, or excess to requirements, and then broken down and recycled. Preventing this autophagy is known to have negative consequences for other organelles, and researchers here show that this is also true for the endoplasmic reticulum. Much of what is noted in this paper parallels what is known of the relationship between autophagy, aging, and mitochondria, another complex organelle essential to cell function: structural changes with age; shifts in autophagy; changes in function; and the protective role of autophagy.

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.

Link: https://doi.org/10.1101/2024.08.07.607085

Cancers are not as high in the list of major causes of death in our species as one might imagine. In this we differ from laboratory mice, which researchers have fondly referred to as "little cancer factories". Nonetheless, when thinking about the evolution of the mechanisms of aging in any mammalian species, one runs into considerations of the risk of cancer again and again. There is a coin, with regeneration and tissue maintenance on one side and risk of cancer on the other. In long-lived species, evolution has come to a balance between these two sides. In our species a lengthening of life span relative to other primates required a suppression of cancer risk that has given rise to a drawn-out decline in function and increasing burden of cellular senescence.

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.

Link: https://doi.org/10.1101/2024.07.30.24311226

The research and development communities are not good at prioritizing the evaluation and development of combination therapies. The incentives surrounding intellectual property and demands of regulators can explain much of this, and the rest is due to the primary focus on small molecules as a mode of therapy. Any two given small molecules that are individually useful are very likely to interact to produce an overall negative effect, so little work is directed towards speculatively combining drugs.

In the case of aging, however, an effective treatment must involve a package of various approaches to the repair of the cell and tissue damage that drives aging. We might expect these approaches to be more likely act in synergy. That said, it is clear that altering metabolism to slow aging suffers from the small molecule interaction problem, wherein most drugs and supplements that modestly slow aging on their own interact negatively to modestly accelerate aging. The field must focus more upon repair of damage rather than alteration of metabolism if the vision of synergistic therapies is to be realized.

Targeting multiple hallmarks of mammalian aging with combinations of interventions

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.

Studies of the biochemistry of wound healing in species capable of complete regeneration of limbs and organs, such as salamanders and zebrafish, has pointed to differences in the behavior of senescent cells and immune cells such as macrophages during the regenerative process. Senescent cells are created as a result of injury, and cleared soon afterward by immune cells. While they are present, they appear to assist in the processes of regrowth and repair. It is hoped that a sufficient understanding of the biochemistry of proficient regeneration in salamanders and zebrafish will lead to ways to recreate the ability of embryonic mammals to regenerate lost body parts. The capability is clearly there, but lost in adult life.

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.

Link: https://doi.org/10.59368/agingbio.20240021

Older people are less capable of regeneration from injury. On top of that, the heart is one of the least regenerative organs in the body, vulnerable in ways that other muscle tissue is not. Cardiovascular disease leads to heart injury, and the aged body is much less able to compensate than would be the case in a younger individual. These are problems in search of solutions. Even in a world in which the case of cardiovascular disease, the growth of atherosclerotic lesions in blood vessels, is prevented, one would still want to be able to reverse the loss of tissue maintenance and regenerative capacity of the heart.

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.

Link: https://doi.org/10.1016/j.jbc.2024.107682