Fight Aging!

Cells become senescent at some pace throughout the body and throughout life, largely by reaching the Hayflick limit on replication, but also under other circumstances, such as when a cell sustains potentially cancerous mutational damage. A senescent cell ceases replication and actively secretes pro-inflammatory signals that (a) encourage senescence in bystander cells and (b) attract the attention of the immune system to destroy the senescent cell. This is all find so long as the immune system can destroy senescent cells rapidly enough to prevent their accumulation, but this stops being the case in later life as the immune system declines in effectiveness. Senescent cells accumulate and become disruptive to tissue structure and function.

Researchers have in the past shown that introducing senescent cells into joint tissue in mice is enough to induce or accelerate osteoarthritis. In today's open access paper, researchers report on the introduction of senescent cells into the skin of 3 month old mice, followed by assessment of a range of measures of health 5 months later. Mouse age doesn't linearly relate to human age, but this is roughly equivalent to the range of early 20s to early 40s in humans. One would not expect to see dramatic signs of aging in 8 month old mice, but there are measurable differences, declines in function. This study demonstrates that the presence of a greater burden of senescent cells makes those declines worse.

Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters.

Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.

A limitation of our study is that the amount and composition of transplanted senescent cells does not accurately reflect senescent cell accumulation during physiological aging. Future research should include other models of senescence induction in the skin, including exposure to physiological levels of UV irradiation. Furthermore, to determine whether paracrine senescence is the causal factor driving the observed aging phenotypes, experiments involving the clearance of senescent cells using senolytic drugs or genetic models that enable the removal of p16 or p21 positive cells should be conducted. In addition, further research is needed to pinpoint which factors released by senescent cells in the skin drive the systemic effects observed in host tissues. Such mechanistic studies could open new avenues for therapeutic intervention.

The most well-studied mouse models of extended life span resulting from disrupted growth hormone signaling involve genetic changes that likely do more than just affect growth hormone metabolism. The usual challenges of cellular biochemistry apply, in that most proteins have more than one function. Here, researchers show that a selective knockout of only growth hormone still extends life, but not to the same extent as is observed in the better known models. Looking at the broader context of the influence of growth hormone metabolism on aging, it is worth recalling that the analogous human loss of function mutants, the condition known as Laron syndrome, do not appear to live notably longer than the rest of the population. As is the case for calorie restriction, effects in short lived species are larger than those in long-lived species such as our own.

The somatotrophic axis, comprised of growth hormone (GH) and GH-releasing hormone (GHRH) secreted from the pituitary or hypothalamus, respectively, is a powerful determinant of laboratory mouse longevity evidenced by the dramatic lifespan extensions that result from genetic interruption at any level of this axis in mice. This body of work suggests that the action of GH is a critical regulator of mammalian lifespan. A crucial limitation of these studies, however, is that mice typically treated as "GH-deficient" display defects in several other genes and hormones which leaves the direct contribution of GH unexplored.

Ames dwarf and Snell dwarf mice, deficient for GH as well as prolactin and thyroid-stimulating hormone, were among the first mice with defective somatotrophic signaling found to be long-lived. Mutant mice lacking a functional GHRH-receptor or functional GHRH also cannot be considered true models of "isolated GH deficiency" as the extrapituitary effects of GHRH, which have gained appreciation as important physiological regulators, could contribute to the lifespan extension reported in these mice. Additionally, mice with a targeted disruption of the GH-receptor (GHR) gene display dramatically elevated levels of GH.

To address this critical gap in knowledge, we carried out the first assessment (to our knowledge) of lifespan in mice with a targeted GH gene knockout in conjunction with metabolic assessment during adulthood. GH knockout (KO) mice maintained under specific pathogen-free conditions with ad-libitum access to standard rodent diet and water displayed a 21% extension in median lifespan over wild type littermates. It is noteworthy that while the differences in lifespan we observed between KO and wild type mice were significant, they are lesser in magnitude than the 40+% extensions reported in other models of somatotrophic disruption. This suggests that while GH deficiency clearly contributes to lifespan extension, an additive effect of additional gene/hormone deficiencies on lifespan may also exist.

Link: https://doi.org/10.1101/2024.09.18.613718

Evidence from animal studies strongly suggests an important role for cellular senescence in supporting cell populations in the brain in driving the onset and progression of age-related neurodegenerative conditions. Senescent cells accumulate with age in tissues throughout the body, the result of growing cell stress resulting from the molecular damage and disarray of aging on the one hand, but on the other hand also the problem of inefficient clearance, resulting from the growing inability of the immune system to destroy senescent cells in a timely fashion. Senescent cells energetically secrete a pro-inflammatory mix of signals, disruptive to tissue structure and function when sustained over the long term.

The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression.

Recent research has linked disease-associated microglia to their transition into a senescent state - characterized by irreversible cell cycle arrest - in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets.

This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

Link: https://doi.org/10.1002/nep3.56

Both calorie restriction and intermittent fasting slow aging and extend life in short-lived mammals. In the short term, many measures of health are improved. In long-lived mammals such as our own species, the short term effects are very similar, but effects on life span are much smaller. The reasons why this is the case remain to be determined. Cellular biochemistry is enormously complex and calorie restriction and fasting produce sweeping changes in near every aspect of the operation of metabolism. Researchers can point to improvements in autophagy as the likely primary mechanism for benefits, but do not have an understanding as to why improved autophagy affects life span so differently in short-lived versus long-lived mammals.

Studies conducted separately to assess the effects of calorie restriction and intermittent fasting in rodents have generally indicated that calorie restriction has a larger effect on aging and longevity. Today's open access paper reports on a direct comparison between the two strategies in the same study, and comes to much the same conclusion. One novel aspect of the research is the use of genetically diverse mice known as diversity outbred mice, a model more representative of the differences in a natural population of mammals than is the case for the usual lineages with carefully cultivated similar genetics between individuals. This led to some interesting insights into differential effects of low calorie intake between mice with different characteristics.

Dietary restriction impacts health and lifespan of genetically diverse mice

Caloric restriction extends healthy lifespan in multiple species. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice.

We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling, an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life.

Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

The choroid plexus is a structure responsible for producing and filtering cerebrospinal fluid, but likely has other important roles as well. The production of cerebrospinal fluid declines with age for reasons that are not all that well explored. A reduced flow of cerebrospinal fluid through the brain likely contributes to brain aging via an increased presence of the metabolic waste that is normally drained from the brain via cerebrospinal fluid flow. Hence the occasional paper such as this one, in which researchers attempt to make some inroads into mapping the age-related biochemical changes that take place in cells of the choroid plexus, one small step along the way to the construction of a bigger picture view of how aging affects the choroid plexus.

The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1).

CSF is composed of 99% water, and the remaining 1% is accounted for by proteins, ions, neurotransmitters, and glucose. A high water permeability of the blood-cerebrospinal fluid barrier (BCSFB), a physicochemical barrier established by choroid plexus (CP) epithelial cells, is essential for the optimal production of the CSF, and this is met by the abundant expression of water channels AQP4 and AQP1. CSF enters from the perivascular spaces surrounding arteries into the brain parenchyma through the AQP4 water channels in the astrocytic end-feet. AQP1 is a cGMP-gated cation channel that serves as a water channel and a gated ion channel in the choroid plexus, contributing to the regulation of CSF production.

Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJPs were also reduced in aged mice.

Our study highlights transcriptional level changes in the CP during aging. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.

Link: https://doi.org/10.1186/s12987-024-00574-0

A growing body of evidence suggests that composition of the gut microbiome - and changes in that composition - may be as influential on long-term health, aging, and age-related disease as well explored lifestyle factors such as exercise. Given the ability to cheaply and accurately determine the identity and size of microbial populations making up the gut microbiome via 16s rRNA sequencing, researchers are finding that many specific aspects of the microbiome both change with age and correlate with specific age-related diseases. The next step is to build robust approaches to producing permanent change in the gut microbiome, such as that achieved via fecal microbiota transplantation from a young donor to an old recipient, but with greater control over exactly what is delivered and the intended outcome.

With the introduction of novel molecular biological techniques and advances in next-generation sequencing technologies, we finally have a snapshot of the gut microbiome and its taxonomical and functional constituents. Various studies have been conducted on healthy elderly individuals to characterize their gut microbiome composition and identify alterations that help delay the onset of age-associated disorders. Although aging is a complex biological process that has yet to be fully understood, we have an increasing volume of evidence supporting the existence of a dialogue between the gut microbiome of a host and its aging process. Aging brings about changes in the gut microbiome, disrupting its balance and functionality, which can accelerate senescence through inflammatory processes and reduced production of beneficial metabolites.

Advancements in the different "omics" fields have provided us with a clear understanding of various host-microbe interactions and their influences on aging. Enrichment of certain taxa, such as Bifidobacterium, Christensenellaceae, and Akkermansia, has been shown to promote longevity and improve quality of life during senescence. To improve the gut microbiome and encourage healthy aging, techniques such as fecal microbiome transplantation (FMT) and oral probiotic treatment have been used. Administration of prebiotics and probiotics may mitigate age-related alterations linked to sarcopenia and longevity.

Since age-related disorders are known to increase intestinal permeability, regaining intestinal permeability by FMT may be a regenerative and successful medicinal technique in producing stem cells for the elderly. Nevertheless, more research is needed to determine whether FMT to old recipients from young donors restores the ability of stem cells to self-renew, regenerate, and differentiate, thereby improving lifespan. To pave the way for discovering therapeutic medications for extending lifespan and treating disorders linked to aging, more research into the interactions between intestinal stem cells and the microbiome is necessary.

Link: https://dx.doi.org/10.14218/ERHM.2024.00008

The categorization of cell states into neat taxonomy is an attempt to conceptually simplify a much more complex, analog underlying reality. Any two cells in a given category may be different in ways that turn out to be meaningful in some contexts. So it should be taken as read that the senescent cells that grow in number with age and contribute to age-related disease differ from one another in many ways, and that what we call senescence is at present an oversimplified big tent. It may well turn out require separation into smaller categories to aid continued research and development into ways to reduce the impact of cellular senescence on later life health.

Better understanding the many differences that can exist between any two given senescent cells is of great interest to researchers who are attempting to produce novel senolytic therapies that can selectively destroy these cells. The existing better explored target mechanisms of first generation senolytic drugs produce variable efficacy in clearance of senescent cells depending on tissue type, duration of senescence, reasons for the onset of senescence, and no doubt many other aspects of senescent biochemistry. The best senolytics to date clear only a fraction of senescent cells, that fraction varying by tissue. In today's open access paper, researchers present a view of cellular senescence as an emergent phenomenon driven by a range of distinct stress response packages, a step on the road to better understanding how to produce better senolytic therapies.

Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity

Cellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity (β-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells.

Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples. Genes regulating stress responses - including transcription factors and genes controlling chromatin accessibility - are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner.

We propose that 'senescence' cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, transcription factors, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.

Analysis of large omics data sets in the context of aging and mortality proceeds apace in the research community. On the one hand there is the production of aging clocks, algorithmic combinations of omics data generated via machine learning, in the attempt to produce a useful measure of biological age. On the other hand there are related analyses such as the one noted here, in which researchers attempt to correlate specific individual biomarkers obtained from a blood sample to age and mortality. Many, many metabolites circulate in the body, and it is certainly possible that some of these are better biomarkers for specific uses than the present consensus choices.

The plasma metabolome carries dynamic biological signals reflecting personal health status. Previous studies have demonstrated the potential of metabolomic biomarkers for disease and mortality risk prediction. With the availability of low-cost, standardized, high-throughput nuclear magnetic resonance (NMR) metabolomic profiling and the promotion of blood tests during medical checkups, the identification and quantification of aging-related metabolomic biomarkers hold potential for personalized health monitoring and anti-aging interventions.

Here, we present the largest aging-related metabolomic profile to date based on 325 NMR biomarkers from 250,341 individuals from the UK Biobank. A subset of 54 aging-related representative metabolomic biomarkers were identified based on their ability to predict all-cause mortality. These aging-related biomarkers are involved in diverse biological functions and metabolic pathways, which might serve as potential anti-aging intervention targets and facilitate further exploration of the mechanism of aging-related diseases. High-resolution analysis of the refined composition and structure of multiple lipoprotein-related biomarkers, enabled by NMR profiling, contributes greatly to unraveling the roles of lipid metabolism in the process of aging.

Link: https://doi.org/10.1038/s41467-024-52310-9

Channels by which cerebrospinal fluid leaves the brain are important to long term health, as they allow removal of metabolic waste such as the protein aggregates that characterize neurodegenerative conditions. It is thought that atrophy of these channels, including (a) passage through the cribriform plate and (b) the comparatively recently discovered glymphatic system, contributes to the aging of the brain by allowing molecular waste to build up to levels that change cell behavior for the worse. Here researchers repeat in human patients the demonstrations of glymphatic drainage of cerebrospinal fluid that have been carried out in laboratory animals. Leucadia Therapeutics is developing an implant to restore passage through the cribriform plate, but it remains to be seen as to how the more complex dysfunction of the glymphatic system will be best addressed.

The glymphatic pathway was described as a network of perivascular spaces (PVS) that facilitates the organized movement of cerebrospinal fluid (CSF) between the subarachnoid space and brain parenchyma. CSF mixes with interstitial fluid, promoting clearance of soluble by-products from the central nervous system. This is suspected to be impaired in sleep dysfunction, traumatic brain injury, and Alzheimer's disease.

Pioneering glymphatic studies in rodents showed CSF tracer flow through the subarachnoid space and into brain parenchyma along periarterial spaces. Human intrathecal contrast-enhanced MRI similarly demonstrated parenchymal contrast enhancement in a centripetal pattern from the subarachnoid space, providing early evidence for human glymphatic function. The PVS is postulated to be involved in this process, yet perivascular CSF tracer transport has not been observed in humans. This is a proof-of-principle study in which, by using intrathecal gadolinium contrast-enhanced MRI, we show that contrast-enhanced CSF moves through the PVS into the parenchyma, supporting the existence of a glymphatic pathway in humans.

Link: https://doi.org/10.1073/pnas.2407246121

Progress in medicine is painfully slow, in part thanks to the perverse incentives that drag down every heavily regulated field. But seven decades are left before we reach the closing years of this century. Seventy years in medicine is a long time. Consider what the medical science of the 1950s looked like in practice; consider what the treatment options looked like for common age-related diseases in that era, where they existed at all. Given that a longevity industry is just getting started, barely a decade old at this point, it seems a strange idea to bet against sizable gains in human life span before the end of the century. Even we play it safe and suggest that it will take a good 20 years or more to measure the degree to which novel forms of therapy extend healthy life in human patients, that still leaves a good long time for the research and development of rejuvenation therapies aimed at the repair of forms of molecular damage that cause aging.

Still, one can't argue against the diminishing returns produced by the old way of doing things when it comes to treatment and prevention of age-related disease. That encompasses public health measures aimed at reducing smoking (and now obesity, the largest problem of our era, as smoking was the largest problem of a past one), improved wealth, and the introduction of therapies that can modestly slow or reduce some of the consequences of aging without actually addressing its causes. Medicine that reduces blood pressure or lowers LDL-cholesterol, for example. Both are influential in the populations that use it, when considered from an epidemiological viewpoint where a 10-20% risk reduction is sizable across a population. But for an individual, a 10-20% risk reduction isn't all that great. It certainly isn't rejuvenation. But that is what the old approach to age-related disease gave us, marginal therapies, marginal outcomes.

The reason that betting against radical life extension seems foolish is that there are now earnest efforts underway to treat aging as a medical condition, a whole new approach to the problem of age-related disease. None of this has yet to reach the clinic in any widespread way, so who knows how effective the initial therapies will turn out to be. On balance, and over the course of decades, one would have to think that a biotech industry actively trying to slow and reverse aging by addressing its causes will make significantly greater progress towards longer healthy lives than a medical industry that was only trying to treat the symptoms of aging.

Implausibility of radical life extension in humans in the twenty-first century

More than three decades have passed since predictions were made about the upper limits to human longevity. Evidence presented here based on observed mortality trends in the worldʼs eight longest-lived populations and in Hong Kong and the United States, and metrics of life table entropy, indicate that it has become progressively more difficult to increase life expectancy. At ages 65 and older, the observed average rate of improvement in old-age mortality in the longest-lived populations evaluated here was 30.2% from 1990 to 2019. The impact of this level of mortality improvement, if experienced again over the next three decades, would yield only a 2.5-year increase in life expectancy at birth. This is a fraction of the 3-year per decade (for example, 8.7-year increase from 1990 to 2019) gain in life expectancy predicted by those claiming that radical life extension was forthcoming or already here. That is, old-age mortality has not been declining since 1990 at a pace that is even close to the rate of improvement required to achieve radical life extension in this century.

Where uncertainty remains is how much more survival time can be manufactured with the disease model that now prevails (shown here to have a declining influence on life expectancy) and the far greater uncertainty associated with future improvements in survival that may result from the deployment of gerotherapeutics or other advances in medicine that cannot be conceived of today. Because radical lifespan extension brought forth by yet-to-be-developed medical advances cannot be empirically evaluated over short timeframes, a limitation here (and within the field of aging in general) is that it is difficult to justify any numerical estimate of their future influence on life expectancy.

Forecasts about radical life extension in humans thought to be occurring now or projected to do so in the near term have already influenced the operations and financial structure of multiple industries. Results presented here indicate that there is no evidence to support the suggestion that most newborns today will live to age 100 because this would first require accelerated reductions in death rates at older ages (the exact opposite of the deceleration that has occurred in the last three decades). Furthermore, even if the 30.2% improvements in mortality in the 65-and-older population observed to have occurred in high-income nations from 1990 to 2019 occurred again, only a small fractional increase in survival to age 100 would ensue.

The evidence presented here indicates that the era of rapid increases in human life expectancy due to the first longevity revolution has ended. Given rapid advances now occurring in geroscience, there is reason to be optimistic that a second longevity revolution is approaching in the form of modern efforts to slow biological aging, offering humanity a second chance at altering the course of human survival. However, until it becomes possible to modulate the biological rate of aging and fundamentally alter the primary factors that drive human health and longevity, radical life extension in already long-lived national populations remains implausible in this century.

If there were a reliable way to prevent metastasis, the spread of cancerous cells throughout the body and generation of secondary tumors, few types of cancer would be life-threatening in the context of today's medical capabilities. Thus there is a lot to be said for the various lines of research aimed at finding ways to sabotage metastasis. Here researchers attempt to answer the question of why migrated metastatic cells sometimes fail to establish a secondary tumor, and point to a population of immune cells that may prove to be a useful target for anti-metatasis immunotherapy.

Cells that migrate from primary tumors and seed metastatic tumors are called disseminated cancer cells (DCCs). Some DCCs behave aggressively, immediately starting tumors in new tissue, while others remain in a state of suspended animation referred to as dormancy. "It's long been a mystery how some DCCs can remain in tissues for decades and never cause metastases, and we believe we've found the explanation." Breast cancer and many other types of cancer metastasize to the lungs. In research involving three mouse models of metastatic breast cancer, researchers determined that when breast cancer DCCs spread to the lung's alveoli, they are kept in a dormant state by immune cells known as alveolar macrophages.

Confirming the importance of alveolar macrophages in keeping DCCs dormant, researchers found that depleting them in the mice significantly increased the number of activated DCCs and subsequent metastases in their lungs compared to mice with normal levels of the immune cells. As DCCs become more aggressive, the researchers found, they become resistant to the pro-dormancy signals produced by alveolar macrophages. Ultimately, this evasion mechanism enables some DCCs to "wake up" from dormancy and reactivate to form metastases. Understanding how immune cells keep DCCs in check could lead to new anti-metastatic cell therapies among other strategies. For example, it may be possible to strengthen macrophage signaling so that DCCs never awaken from dormancy or find ways to prevent older DCCs from becoming resistant to dormancy signaling.

Link: https://www.eurekalert.org/news-releases/1060251

Researchers can use the strategy of Mendelian randomization to attempt to explore causation in human epidemiological data, provided that data includes information on gene variants associated with the outcomes of interest. Here, this approach is used to gain some insight into the direction of causation in the relationship between epigenetic age acceleration, an epigenetic age greater than chronological age, and the incidence of neurodegenerative conditions such as Alzheimer's disease.

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age, GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge, (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6,618 to 482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (inverse-variance-weighted, IVW beta = -0.309). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD.

In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.

Link: https://doi.org/10.1111/acel.14271

Past studies have demonstrated that the economic cost of aging is enormous. It is not just a matter of the high medical cost of coping with a failing body and a panoply of conditions that cannot presently be cured or even much reversed. The lifetime cost of treating only cardiovascular disease is something like $750,000, for example. There is also the constant destruction of knowledge, capability, and ability to work. There is the opportunity cost of actions that cannot be taken. If everyone in the US gained a year of additional life, if aging was slowed by one year, $38 trillion in economic gains per year would be realized. These are staggering numbers.

In today's open access papers, the authors take a different approach to looking at the value of treating aging as a medical condition. What if every region of the world could adopt the age-related mortality of the best performing region? For each major cause of aging the authors take mortality rates in the best performing region as a benchmark, and consider mortality above this level to be avoidable. Which may or may not be entirely the case, but it is a decent place to start if running the numbers on what an incremental, near future advance in the treatment of aging might look like. As one might expect, the numbers are still very large.

Why do the differences between regions exist? Largely lifestyle choices, and then a layer of socioeconomic status and access to medical technologies on top of that. When it comes to cardiovascular disease risk, the average American is not outperforming the average Bolivian hunter-gatherer, despite the vast disparity in wealth. So strictly speaking, this isn't a discussion about medical technology. Nonetheless, the numbers are interesting in a world in which we may expect the near future introduction of treatments for aging that could have similar effect sizes to exercise, calorie restriction, weight loss, and other lifestyle considerations.

The economic value of reducing avoidable mortality

Living longer and healthier boosts individual and family welfare. As part of the World Bank's Healthy Longevity Initiative, we quantified the economic value of achieving the highest possible life span. We estimated the economic value of reducing avoidable mortality, defined as the difference between observed (or projected) mortality and lowest achieved (or projected) mortality, by world regions, sex, and age, between 2000 and 2021, with projection to 2050.

In 2019, 69% of mortality, or 40 million deaths, was avoidable. The economic value of avoidable mortality globally was 23% of annual income, meaning that, globally, populations would be willing to give up about one-fifth of their current income in exchange for a year living at the lowest achieved mortality rate. This value ranges from 19% in China to 34% in sub-Saharan Africa. Under the rapid-progress scenario, in which countries experience fast but plausible mortality reductions from 2019 to 2050, we would expect globally the gap between projected and frontier life expectancy to be halved by 2050, and the economic value after achieving this scenario is equivalent to 14% of annual income. Our work provides supportive evidence on the high economic value placed on improving health.

The economic value of reducing mortality due to noncommunicable diseases and injuries

With population aging, national health systems face difficult trade-offs in allocating resources. The World Bank launched the Healthy Longevity Initiative to generate evidence for investing in policies that can improve healthy longevity and human capital. As part of this initiative, we quantified the economic value of reducing avoidable mortality from major noncommunicable diseases and injuries. We estimated avoidable mortality - the difference between lowest-achieved mortality frontiers and projected mortality trajectories - for each cause of death, for 2000, 2019 and 2050, and for geographic regions, with high-income countries, India and China considered separately; we applied economic values to these estimates.

The economic value of reducing cardiovascular disease avoidable mortality would be large for both sexes in all regions, reaching 2-8% of annual income in 2019. For cancers, it would be 5-6% of annual income in high-income countries and China, and for injuries, it would be around 5% in sub-Saharan Africa and Latin America and the Caribbean. Despite the large uncertainty surrounding our estimates, we offer economic values for reducing avoidable mortality by cause and metrics comparable to annual incomes, which enable multisectoral priority setting and are relevant for high-level policy discussions around budget and resource allocations.

The interior of blood vessels is lined by the endothelium. With aging, cells of the endothelium exhibit stress, inflammation, and altered behavior, contributing to the development of atherosclerosis and negatively affecting performance of the vasculature. Here, researchers discuss the degree to which this aspect of degenerative aging is caused by the presence of senescent cells. Cells become senescent constantly throughout life, but in youth are cleared efficiently by the immune system. This clearance falters later in life, allowing senescent cells to grow in number to the point of becoming disruptive to tissue structure and function. Senolytic therapies to selectively clear senescent cells have proven to be beneficial in animal studies and are presently in human trials for a number of age-related conditions.

Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence.

We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-β-Gal was quantified. We found a negative correlation in passaged cell cultures between a reduction in NO production with increased ES and the formation of reactive oxygen species and reactive nitrogen species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN).

Thus NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response.

Link: https://doi.org/10.3390/ijms25189890

The metabolic responses to exercise and calorie restriction are so sweeping that there are many, many possible avenues by which drugs can mimic some of the effects. Researchers here try to get closer to the roots of these beneficial responses by using a molecule that will trigger the same reactions as two circulating signal molecules known to be important in regulating the response to exercise and fasting. This seems a reasonable strategy to try to capture a larger fraction of the benefits of exercise and fasting, but of course much more work is needed in order to see how this approach matches up to the sizable number of existing exercise mimetic and calorie restriction mimetic interventions.

Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest.

In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).

Link: https://doi.org/10.1021/acs.jafc.4c04849