Fight Aging! Newsletter, October 14th 2024

Biostasis is the practice of preservation of humans for the long-term with the intent of future recovery, if this ever becomes feasible. Biostasis can be distinguished into two hypothetical modalities: (a) provably reversible preservation and (b) preservation of informational features in the body in a way that is not reversible with currently known technologies, with the hope that such technologies can be developed and implemented in the future. Provably reversible preservation, also known as suspended animation, is not yet possible for humans, and probably will not be possible anytime soon, absent incredibly rapid advances in preservation technology. Yet, contemporary biostasis methods do not need to be proved to be reversible now in order to allow for a potential chance at revival in the future. The primary justification of contemporary biostasis, which we adopt here, is the preservation of the brain, which most consider to be the seat of our memories, personalities, and identities. By preserving the information contained within the structures of the brain, we may one day be able to revive the individual using advanced future technologies, even though this would require society to bootstrap the development of those technologies while individuals remain under preservation. This practice is also called neural biostasis, brain preservation, or brain archiving. We use the more general term biostasis in this roadmap.

This roadmap is divided into seven main categories: pre-cardiac arrest factors, post-cardiac arrest stabilization, preservation compounds, preservation procedures, methods for measuring preservation quality, long-term preservation, and restoration and recovery. We have attempted to outline the current state of research and future directions for the field of biostasis, with a focus on the scientific and technical aspects of brain preservation for potential future revival. This roadmap touches on several directions, including the development of better chemical compounds and better delivery approaches for those chemicals. Continued research into platforms and chemicals that could improve neural tissue preservation, alongside research into surgical techniques, cannulation methods, perfusion parameters, and long-term storage methods, would all be enormously valuable.

Economic factors are crucial for any field of scientific research, and biostasis research is no exception. So far, funding for biostasis research has predominantly come from individuals and organizations with a vested interest in the field, such as cryonics companies and individual cryonicists. While this has allowed for some progress, the limited resources have constrained the scope and pace of research. To the best of our knowledge, there has never been specific funding awarded for biostasis research from any government agency. We believe that for the field to grow and reach its full potential, there is a need for funding from larger sources, such as government agencies, academic institutions, and philanthropic organizations without a specific focus on biostasis. However, this expansion of funding sources faces a significant challenge: many potential funders and members of the public are highly skeptical about the feasibility of biostasis. This creates a chicken-and-egg problem, where the field receives little funding because many people do not believe it is promising, but there has also been insufficient research to thoroughly investigate its potential.

Breaking this cycle will likely require innovative approaches to both research and public engagement. Possible strategies to address this include: (1) fostering collaborations between biostasis researchers and mainstream cryobiology or neuroscience labs to increase access to resources and the reliability of the research, (2) developing clearer roadmaps and milestones to demonstrate progress and potential, (3) engaging in more public outreach to address misconceptions and discuss ethical concerns, (4) exploring alternative funding models such as crowdfunding or decentralized science initiatives, and (5) leveraging funding for other research topics where synergies with problems relevant to biostasis exist and publishing resulting findings in reputable scientific journals. Additionally, emphasizing the potential spillover benefits of biostasis research to other fields, such as organ preservation for transplantation, treatment of acute brain injuries, or connectomics, could help attract broader interest and support. Overcoming these funding challenges will be critical for performing a thorough and objective examination of the true potential of biostasis technologies.

Current neuroimaging-based approaches to measure aging, akin to first-generation epigenetic clocks, involve training models to predict chronological age from variability in MRI measures of brain structure in large multi-age samples. Researchers then typically quantify a "brain age gap," which reflects the difference between a participant's predicted and actual chronological age. A positive brain age gap is interpreted as evidence of accelerated brain aging. As with first-generation epigenetic clocks, these age-deviation approaches unavoidably mix model error (e.g., historical differences in environmental exposures, survivor bias, disease effects, measurement bias) with a person's true rate of biological aging.

Here, using a single T1-weighted MRI scan collected at age 45 in the Dunedin Study, we describe the development and validation of a novel brain MRI measure for the Pace of Aging. We call this measure the Dunedin Pace of Aging Calculated from NeuroImaging or "DunedinPACNI." Using data from the Human Connectome Project we evaluated the test-retest reliability of DunedinPACNI. Exporting the measure to the Alzheimer's Disease Neuroimaging Initiative (ADNI) and UK Biobank, we conducted a series of preregistered analyses designed to evaluate the utility of DunedinPACNI for predicting multiple aging-related health outcomes. To benchmark our findings, we compared effect sizes for DunedinPACNI to those for brain age gap. DunedinPACNI is the first brain-based measure trained to directly estimate longitudinal aging of non-brain organ systems.

Neuroimaging Initiative and UK Biobank neuroimaging datasets revealed that faster DunedinPACNI predicted participants' cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed the expected socioeconomic health gradient. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a "next generation" MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

Sarcopenia, characterized by age-related decline in muscle mass and function, significantly increases the risk of adverse outcomes such as impaired quality of life, falls, hip fractures, frailty, hospitalization, disability, and mortality. Individuals with sarcopenia have a higher likelihood of premature mortality compared to their age-matched counterparts. Sarcopenia also strongly predicts disability, defined as limitations in activities of daily living (ADL) and care home admissions. However, it is plausible that age-associated modifications in the gut microbiota and muscle tissue composition could be driven by shared underlying processes, such as chronic inflammation, dysfunction of the immune system, and changes in hormone levels, which could influence both microbiota alterations and the onset of sarcopenia.

Currently, there is no single effective therapeutic intervention for sarcopenia. The 'gut-muscle axis', which explores how the gut microbiome affects muscle mass, strength, and function in older adults, plays a crucial role in both the prevention and management of sarcopenia. Previous research indicates that diet composition and the gut microbiome change with age and are correlated with muscle mass decline, thereby impacting physical performance. Advanced age leads to gut microbiome dysbiosis, characterized by altered microbial diversity, predominant bacteria, and reduced beneficial bacterial metabolites. These biological processes, particularly those related to inflammation and the immune system, are greatly influenced by the gut microbiome. Studies show differences in gut microbiome composition, measured using RNA sequencing, between older and younger participants, marked by variations in alpha diversity//en.wikipedia.org/wiki/Alpha_diversity">alpha diversity (species diversity within a sample) and beta diversity (species diversity between samples). Animal studies support these findings, suggesting that variations in the gut microbiome and metagenome influence biological processes such as inflammation, nutrient bioavailability, and lipid metabolism, contributing to age-related muscle decline.

This review provides insight into potential novel interventions for sarcopenia prevention and treatment. A systematic search was conducted for studies published between 2002 and 2022 involving participants aged 50+. Studies were included if they assessed sarcopenia using at least one measure of muscle mass (skeletal muscle mass, bioelectrical impedance analysis, MRI), muscle strength, or muscle performance. The microbiome was measured using at least RNA/DNA sequencing or shotgun metagenomic sequencing. Twelve studies were analyzed. Findings revealed that a higher abundance of bacterial species such as Desulfovibrio piger, and Clostridium symbiosum and reduced diversity of butyrate-producing bacteria was associated with sarcopenia severity, as indicated by decreased grip strength, muscle mass, or physical performance. The gut microbiome plays a significant role in age-related muscle loss. Probiotics, prebiotics, and bacterial products could be potential interventions to improve muscle health in older adults.

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing. Several genetic interventions have been found to ameliorate old brain function, but systematic functional testing of genes in old NSCs - and more generally in old cells - has not been conducted. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice.

Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR-Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age.

Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.

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.

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.

Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer's disease (AD). We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of an animal model of AD.

Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of the LC3B gene and turns on a prolonged transcription of the SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal markers and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.

Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

Although lifespan extension remains the gold standard for assessing interventions proposed to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that short lifespans in the control group exaggerate the relative efficacy of putative longevity interventions. Due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups.

Incorporating many of these suggestions for optimal mouse husbandry and avoiding pitfalls of other lifespan studies, the rigorous National Institute of Aging Interventions Testing Program (ITP) has become a gold-standard for mouse longevity studies. In the ITP, studies are performed on both sexes, with large sample sizes and across three different centers to address idiosyncratic issues of mouse husbandry. Furthermore, the UM-HET3 mice used by the ITP are relatively long-lived compared to most inbred strains and genetically heterogenous, thereby reducing the likelihood that mice die of strain-specific pathologies, a factor that may confound lifespan data.

A majority of compounds tested by the ITP have not been previously published to extend lifespan in mice, thus we lack a "ground truth" for their expected effect size. Notably, however, the ITP has failed to replicate published lifespan extension for several compounds such as metformin, resveratrol, and nicotinamide riboside, raising concerns about the robustness of published mouse longevity data. Although differences in genetic background, age of treatment onset, husbandry, and dosing between the original study and the ITP cohorts may explain replication failures, another potential factor is methodological rigor.

In this manuscript, we reanalyze data from caloric restriction (CR) studies performed in multiple species, the ITP and other large mouse lifespan studies with a particular focus on control lifespan as one potential explanation for inflated effect sizes and lack of replicability. As a solution, we emphasize the importance of long-lived controls in mouse studies which should reach a median lifespan of around 900 ±50 days, or the comparison to appropriate historical controls, and we term this the "900-day rule".

Osteoporosis, sarcopenia, and osteoarthritis, three common musculoskeletal disorders that often coexist in the elderly population. The loss of bone and muscle mass and the progressive degradation of cartilage are the macroscopic effects of the complex pathological processes underlying these diseases, in association with an increased susceptibility to fractures and an elevated risk of falls. From a microscopic point of view, affected tissues are characterized by numerous cellular and molecular alterations that induce a state of replicative senescence, irreversibly compromising the quality of the musculoskeletal system. Not surprisingly, cellular senescence has recently emerged as a critical element in the pathophysiology of osteoporosis, sarcopenia, and osteoarthritis, highlighting the need for further studies to understand the intricate relationship between cellular senescence and musculoskeletal functions, as well as to develop effective strategies to mitigate and manage these debilitating conditions.

Cellular senescence has been suggested to be among the mechanisms responsible for the decline in regenerative function observed in muscle and bone stem cells with advancing age because of the up-regulation of certain proteins, including p16, p21, and p27, responsible for altered tissue metabolism. Particularly, senescent bone cells are known to release the senescence-associated secretory phenotype (SASP) that promotes osteoclast activity, inducing bone resorption and accelerating bone mass loss. In agreement, studies in mouse models have shown that the elimination of senescent cells improves bone mineral density and bone microarchitecture, counteracting the onset of osteoporosis. Furthermore, in skeletal muscle, the senescence of satellite cells, which are essential for muscle regeneration, significantly reduces tissue repair capacity. In this regard, experiments in mouse models have shown that the elimination of senescent cells improves muscle function and increases muscle mass, suggesting senolytics as potential strategies in the treatment of sarcopenia. Finally, the accumulation of senescent cells in joints has been suggested to contribute to cartilage degradation and synovial inflammation, exacerbating the joint deterioration that characterizes osteoarthritis.

Primary osteoarthritis (OA) is a prevalent degenerative joint disease that mostly affects the knee joint. It is a condition that occurs around the world. Because of the aging population and the increase in obesity prevalence, the incidence of primary OA is increasing each year. Joint replacement can completely subside the pain and minimize movement disorders caused by advanced OA, while nonsteroidal drugs and injection of sodium hyaluronate into the joint cavity can only partially relieve the pain; hence, it is critical to search for new methods to treat OA.

Increasing lines of evidence show that primary OA is a chronic inflammatory disorder, with synovial inflammation as the main characteristic. Macrophages, as one of the immune cells, can be polarized to produce M1 (proinflammatory) and M2 (anti-inflammatory) types during synovial inflammation in OA. Following polarization, macrophages do not come in direct contact with chondrocytes; however, they affect chondrocyte metabolism through paracrine production of a significant quantity of inflammatory cytokines, matrix metalloproteinases, and growth factors and thus participate in inducing joint pain, cartilage injury, angiogenesis, and osteophyte formation.

The main pathways that influence the polarization of macrophages are the Toll-like receptor and NF-κB pathways. The study of how macrophage polarization affects OA disease progression has gradually become one of the approaches to prevent and treat OA. Experimental studies have found that the treatment of macrophage polarization in primary OA can effectively relieve synovial inflammation and reduce cartilage damage. The present article summarizes the influence of inflammatory factors secreted by macrophages after polarization on OA disease progression, the main signaling pathways that induce macrophage differentiation, and the role of different polarized types of macrophages in OA; thus, providing a reference for preventing and treating primary OA.

Recent studies have shown that limited use of Yamanaka factors or chemicals that mimic their effects can partially reverse cellular or organismal aging. This has been observed in both in vitro human and mouse models, as well as in vivo mouse studies, without fully de-differentiating cells into a pluripotent state. These studies encompass various models, including healthy aged and diseased mice, such as progeroid mice, and involve pulsed, short-term, and medium-term reprogramming regimes; these we call "partial reprogramming" as long as no induction of pluripotency is observed.

Comparing in vitro and in vivo mouse studies, and in vitro studies in humans, supported by visualizations of the interconnections among the data, we show consistent patterns in how such reprogramming modulates key biological processes. Generally, it leads to enhanced chromatin accessibility, upregulation of chromatin modifiers, and improved mitochondrial activity. These changes are accompanied by shifts in stress response programs, such as inflammation, autophagy, and cellular senescence, as well as dysregulation of extracellular matrix pathways.

Ultimately, until we achieve a more robust understanding of aging at the molecular level - and identify much more reliable biomarkers of biological age - the extent to which reprogramming can reverse aging will remain unclear. The effects and potential side effects of reprogramming are context-dependent, varying with the specifics of the reprogramming protocol (such as duration) and the characteristics of the target, including species and tissue or cell types involved. Nonetheless, reprogramming holds significant promise in reversing various biomarkers of aging.

While earlier first-generation epigenetic aging clocks were trained to estimate chronological age as accurately as possible, more recent next-generation clocks incorporate DNA methylation information more pertinent to health, lifestyle, and/or outcomes. Recently, we produced a non-invasive next-generation epigenetic clock trained using DNA methylation data from more than 8,000 diverse adult buccal samples. While this clock correlated with various health, lifestyle, and disease factors, we did not assess its ability to capture mortality. To address this gap, we applied CheekAge to the longitudinal Lothian Birth Cohorts of 1921 and 1936.

To our knowledge, this is the first study to demonstrate that an aging biomarker optimized for buccal tissue can be applied to blood for mortality prediction. Our findings build on previous work from more than a decade ago, which found that buccal methylation data was highly informative for a variety of phenotypes and diseases. The magnitude of the hazard ratio for mortality prediction outcompetes all first-generation clocks tested and compares favorably to the next-generation blood-trained clock DNAm PhenoAge. These data suggest that adult buccal tissue, which is relatively painless and easy to collect in a variety of settings, may represent a rich source of aging biomarkers.

The study utilized human stem cells to model age-related macular degeneration (AMD), overcoming the limitations of previous research using animal models. By examining genes associated with both AMD and rarer inherited forms of blindness called macular dystrophies, the researchers identified a key protein involved in the early stages of the disease. The retinal pigment epithelium (RPE), a layer of cells at the back of the eye, plays a crucial role in AMD. Over time, deposits of lipids and proteins, known as drusen, accumulate in the RPE. These deposits are often an early indicator of AMD.

The researchers discovered that a protein called tissue inhibitor of metalloproteinases 3 (TIMP3) is overproduced in AMD. TIMP3 inhibits the activity of enzymes called matrix metalloproteinases (MMPs), which are essential for eye health. Impaired MMP activity leads to increase in another enzyme which promotes inflammation and the formation of drusen. By using a small molecule inhibitor to block the activity of the enzyme associated with inflammation, the researchers were able to reduce drusen formation in their model, suggesting that targeting this pathway could be a promising strategy for preventing AMD.

Stroke is a leading cause of disability and dementia worldwide, with projections suggesting a continued rise in its prevalence and burden. Recent studies have shown that cognitive impairment is highly prevalent after stroke, with cognitive deficits present in over a third of stroke survivors. However, the precise impact of stroke on the trajectory of cognitive function remains unclear. Previous studies, primarily hospital-based, have been unable to account for prestroke cognitive performance, and several population-based studies examining prestroke and poststroke cognitive function reported conflicting findings, likely due to variations in study design, sample characteristics, and statistical techniques.

This study aimed to address these inconsistencies by mapping the trajectory of cognitive function after stroke relative to the cognitive trajectory without a previous stroke using harmonized data from diverse population cohorts from the Cohort Studies of Memory in an International Consortium (COSMIC). The study included 20,860 participants with a mean (standard deviation, SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures.

Thus in this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.

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).

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.