Fight Aging!

Senescent cells accumulate with age throughout the body, and cause considerable disruption to tissue structure and function via their pro-inflammatory secretions. Clearing senescent cells is an important approach to rejuvenation and reversal of age-related disease, based on the impressive results produced in mice to date. One of the challenges inherent in the destruction of senescent cells is the variation shown in their biochemistry, depending on how they become senescent and on which tissue they reside in. Different treatments exhibit widely varying outcomes for different varieties of senescent cell, and those varieties are far from fully or comprehensively catalogued.

In today's open access paper, researchers describe a novel approach to the selective destruction of senescent cells, focusing on characteristics of the dysfunctional iron metabolism exhibited by cells that become senescent in response to the signaling of other senescent cells, undergoing what is know as paracrine senescence. The researchers show that should be possible to produce an iron-activated prodrug, in which the active cell-killing drug substance is masked by a chemical addition that is only stripped in cells that exhibit the aberrant iron metabolism characteristic of senescent cells. It is worth noting that prodrugs based on the high levels of β-galactosidase in senescent cells have shown considerable promise to date, so we might expect analogous approaches to be similarly interesting.

Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis

The molecular biology of cellular senescence has opened the possibility of exploiting the differential vulnerabilities of senescent cells (SCs) compared with healthy cells for the development of a new class of longevity therapeutics against aging and age-related disorders. However, the significant heterogeneity among SCs based on cell type of origin or senescence induction method suggests the need to develop senolytics that either have a broader therapeutic efficacy or that can target recalcitrant SCs.

In this context, paracrine senescence (PS) is the least understood type of senescence. Even though there have been previous efforts to characterize PSs, the fact that only a subset of cells exposed to the senescence-associated secretory phenotype (SASP) factors become senescent means that previous experimental protocols were compromised, with mixed cell populations dominated by non-senescent cells labeled as PSs. We were able to circumvent this major methodological issue by isolating and enriching PSs using the previously characterized SC surface marker DPP4.

We discovered that DPP4+ paracrine SCs (PSDPP4+) engage prosurvival pathways that are distinct from those on which DPP4+ primary SCs (SDPP4+) rely and are also relatively resistant to killing by senolytic drugs previously identified to be effective against primary SCs. Given that SCs accumulate ferrous iron (Fe(II), also known as labile iron), we sought to test a Fe(II)-targeting strategy in which Fenton reaction of a prodrug was coupled to release of drug payload. Others previously showed that the tumor-activated prodrug TRX-CBI (comprising a trioxolane-based [TRX] sensor of Fe(II) conjugated to a cytotoxic cyclopropylbenzindoline [CBI] payload) demonstrated selective toxicity in Fe(II)-rich cancer cells.

Here, we used a form of TRX-CBI to target cytotoxic CBI to SCs. We demonstrated that treatment with TRX-CBI triggers significant senolysis of both PSDPP4+ and SDPP4+, with negligible cytotoxicity toward non-senescent cells. Based on our results, we propose Fe(II)-based targeting of SCs with ferroptosis inducers or iron-activated drug conjugates as broad-spectrum senolytic agents.

The primary approach to the prevention and treatment of mitochondrial aging undertaken by the SENS Research Foundation is allotopic expression, putting backup copies of mitochondrial genes into the nuclear genome. This prevents mitochondrial DNA mutations from degrading mitochondrial function in ways that can become pathological. This isn't the only approach on the table, however, and here some of the others are outlined.

Mitochondrial mutations - and above all, large deletions in the mitochondrial DNA - accumulate in long-lived cells over our lifetime. And until we can do something to repair or bypass that problem, the overtaking of this small fraction of our cells by deletion-bearing mitochondria will continue to drive diseases of aging. Long before there was a SENS Research Foundation - even before a "Strategies for Engineered Negligible Senescence" (SENS) platform existed - our founding CSO Dr. Aubrey de Grey surveyed the possible solutions for this problem, and the only one that seemed viable was allotopic expression (AE).

So why - after making great leaps forward with the science - are we now breaking ground on entirely new MitoSENS strategies? A few reasons. Considered at the most fundamental level, AE itself is an inherently difficult biotechnological challenge. Then there's the additional hurdle of delivering it to those cells that are vulnerable to mitochondrial mutations with age. Thus scientists in our MitoSENS lab are now working on two of these alternative strategies - both of them also thought up or endorsed by Dr. de Grey. You might think of them as backup strategies for the backup copies.

One of these strategies is to use a form of mitochondrial transplantation to replace the cell's mutation-bearing mitochondria with healthy ones. For mitochondrial transplantation to work as a rejuvenation biotechnology, we need a way not only to get the transplanted mitochondria into the cells, but to enable them to bypass the selective advantage of the native mitochondria, and especially of the powerful advantage of mutation-bearing mitochondria. This is where the relatively new biotechnology of "gene drives" come in. Engineered mitochondria would use restriction enzymes designed to target one of the several restriction sites that are naturally present in the host's mitochondria. The restriction enzyme would quickly go to work eviscerating the cell's original mitochondrial DNA, thereby clearing space to allow the new, transplanted mitochondria to take over.

We can't say much about the second strategy the MitoSENS team is exploring because it's a very early-stage project, and we want to be sure we're on the right track before making any announcements. All we'll say for now is that our scientists have identified a drug that may potentially "unmask" deletion-bearing mitochondria, attracting the attention of the mitophagy machinery and allowing it to cull them. Under some circumstances, such "unmasking" is sufficient to keep deletion-bearing mitochondria at bay when they haven't yet overtaken the cell. If the drug we're testing (or a similar one) could do that, we might be able to keep many cells operating normally by holding deletion-bearing mitochondria down to a minority of the population, and keep other cells free of deletion-bearing mitochondria entirely by catching the first one and sending it to its grave.

Link: https://www.sens.org/mitosens-new-strategies-gene-drive-mitophagy/

This article lists a variety of types of activity and project that might be undertaken to help to speed up the development of ways to treat aging as a medical condition. If you don't have a background in the life sciences, but nonetheless find human longevity a compelling topic, and would like to work in the field, what can you do? That is a good question, and often asked. There are many options that don't involve working as a scientist in a laboratory, though educating yourself about the science helps a great deal when it comes to picking the better options from the array of choices on the table.

Aging is a set of molecular and cellular processes that affects us all, but what if we could extend our healthy lifespan and live longer, healthier lives? This is the goal of the rapidly growing field of longevity. And after my last post about leaving my CTO job to work on longevity a lot of people have reached out asking what I'm working on actually? What I'm building for longevity? The short answer is... nothing. Yet. The long answer is... well, this post. I believe that anyone can work on anything they put their mind to if they are willing to put in the time and effort to learn the necessary skills. Whether it's research, funding, talent, media, practical longevity, aging therapeutics, or infrastructure, there are numerous opportunities to make a significant impact in this field.

$6.96 billion was raised across 96 funding rounds in 2022. This may seem like a lot but it's actually nothing. Remember that Instagram was acquired for $1 billion. So trying to bring more funding to the longevity field is very much needed. Someone needs to help talented people transition into the field. And believe me, we need far, far more people working on longevity. Recruiting and community building are important. The narrative around longevity is changing towards a more strategic conservatism which is proving to have better adoption. But it's far away from reaching a mainstream level. We need more communicators designing and evolving new narratives for different people.

The first drug targeted to extend healthy lifespan by 10-20 years could be developed and commercialized this decade. Aging therapeutics usually means getting the science out of the lab. So most often than not, someone with biology background will try to start or join a startup around their expertise. But what about people who are not coming from academia? The reality is that it may take anything from 6 months to 1 year (maybe even more) of full dedication to gain enough context, map the gaps, understand low hanging fruits, understand which technologies are the most promising, and get in love with a strong hypothesis to join or build a startup around it. This is the hardest part: in an ocean of possibilities, which one to choose? Which one is the most interesting? What technology is the most promising? What are the low hanging fruits?

Link: https://www.stanete.com/work-on-longevity/

Angiogenesis is the process of building new blood vessels in response to circumstances, such as a relative lack of oxygenation in tissues, or repair of injury. It is quite complicated, involving several distinct stages and the interactions of a variety of different cell populations. Angiogenesis declines with age, particularly in the context of maintaining capillaries. The density of capillary networks is reduced with age, and this may be quite influential in the aging of energy-hungry issues such as the brain and muscles. It isn't just a reduction in delivery of nutrients and oxygen. Loss of microvascular blood flow through tissues is likely also disruptive to the regulation of blood pressure, a factor contributing to the development of hypertension.

Which of the mechanisms of aging contribute to the loss of angiogenesis with age? Endothelial progenitor cells are one of the cell populations involved in angiogensis. In today's open access paper, the authors discuss cellular senescence in this population, and its negative effects on the capacity for angiogenesis, through the lens of microRNA regulation of these processes. Senescent cells grow in number with advancing age, in cell populations throughout the body. Their presence alters the cellular environment for the worse, generating inflammation and altered cell behavior. The research here provides just one example of many.

Hsa-miR-409-3p regulates endothelial progenitor senescence via PP2A-P38 and is a potential ageing marker in humans

Endothelial progenitor cells (EPCs), obtained from peripheral blood and identified as CD34 antigen-positive (CD34+) mononuclear cells, were marrow-derived stem cells and can differentiate into endothelial cells to promote neovascularisation in response to ischemic injury. Cell therapy using EPCs has been shown beneficial in ischaemia-related cardiovascular diseases (CVD) and emerged as useful substrates for neovascularization. However, some limitations make their clinical application difficult, such as heterogeneity in progenitor cell types, lack of standardization of specific surface markers and reduced number during ageing. Nonetheless, the angiogenic potential of EPCs has been an important target in regenerative medicine.

Numerous studies indicated that microRNA (miR or miRNA) is involved in post-transcriptional regulation of gene expression concerning diverse biological functions, including ageing and angiogenesis. A previous report showed that angiogenesis and tissue repair were regulated by miRNA-135a-3p via targeting p38 signalling in endothelial cells, revealing a link among miRNA, angiogenesis, and endothelial cells. In addition, increased miRNA-183-5p with age was involved in stem cell senescence. Furthermore, several studies have also addressed the regulation of miRNA during culture-induced senescence of vascular cells or in tissues.

These findings suggested that senescence and miRNAs may play an integrated role in modulating the pathologic processes of human CVD via the regulation of progenitor cell activity. We, therefore, in the present study explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with PP2A siRNA caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs.

Inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis by regulating PP2A/p38 signalling.

In order to live longer, one needs to be more healthy, less impacted by dysfunction and damage, suffer fewer outright age-related diseases. This is what one sees when assessing centenarians against the average of the oldest populations. Aging is damage, and age-related disease is the manifestation of that damage. Different people age at different rates, largely the consequence of lifestyle choice and environmental factors such as exposure to persistent pathogens. It is also possible that genetic variants become more important in very late life by providing greater resilience, but so far the weight of evidence leans more towards lifestyle choice and luck when it comes to the small number of individuals who do survive to a century of age.

Centenarians exhibit extreme longevity and have been postulated, by some researchers, as a model for healthy aging. The identification of the characteristics of centenarians might be useful to understand the process of human aging. In this retrospective study, we took advantage of demographic, clinical, biological, and functional data of deceased individuals between 2014 and 2020 taken from the Basque Health Service electronic health records data lake. Fifty characteristics derived from demographic, clinical, pharmaceutical, biological, and functional data were studied in the descriptive analysis and compared through differences in means tests. Twenty-seven of them were used to build machine learning models in the predictive analysis and their relevance for classifying centenarians was assessed.

Most centenarians were women and lived in nursing homes. Importantly, they developed fewer diseases, took fewer drugs, and required fewer medical attendances. They also showed better biological profiles, exhibiting lower levels of glucose, hemoglobin, glycosylated hemoglobin, and triglycerides in blood analysis compared with non-centenarians. In addition, machine learning analyses revealed the main characteristics of the profiles associated with centenarians' status as being women, having fewer consultations, having fewer diagnoses of neoplasms, and having lower levels of hemoglobin.

Link: https://doi.org/10.3389/fpubh.2022.1096837

Researchers here discuss the proposal that Alzheimer's disease results from high sugar and glycemic carbohydrate intake. It is certainly possible that this mechanism contributes, but one has to ask why, if this was a dominant mechanism, is lifestyle much less correlated with Alzheimer's incidence than is the case for common metabolic diseases such as type 2 diabetes? One of the challenges all along with Alzheimer's is that it doesn't have a strong enough correlation with metabolic dysfunction and lifestyle choice to believe that it can be wholly, or even largely, a metabolic condition.

An important aspect of survival is to assure enough food, water, and oxygen. Here, we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose, which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in a resting human amounts to 20% of the overall energy demand, is only beginning to be understood.

Here, we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimer's disease and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged in multiple ways, including diets high in sugar, high glycemic carbohydrates, and salt. In summary, we propose that Alzheimer's disease may be the consequence of a maladaptation to an evolutionary-based survival pathway and what had served to enhance survival acutely becomes injurious when engaged for extensive periods. Although more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimer's disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine whether there is potential benefit in the prevention, management, or treatment of this disease.

Link: https://doi.org/10.1016/j.ajcnut.2023.01.002

Supercentenarians, much as one might expect, exhibit signs of being biologically younger than their years. It is a lower burden of age-related damage and dysfunction that allows them the chance to survive. That said, it is worth noting that many characteristics so far observed in studies of supercentenarians are also present in large numbers of people who die well before reaching a century of life. The fortunately biochemistry of supercentarians adjusts small odds of survival to be slightly more favorable, but still small odds of survival. It is far from an assurance, and it certainly doesn't prevent one from becoming frail and dependent. Supercentenarians are greatly impacted by aging, exhibiting a roughly 50% yearly mortality rate.

For these reasons, efforts to better understand the survival of supercentenarians seem to me to be a matter of scientific interest, but not a matter of practical interest. It is not the path that will lead to ways of ensuring meaningfully greater health and longevity for all. Today's open access paper is an example of this sort of research, a deeper dive into differences in epigenetic patterns exhibited in supercentenarians. Epigenetic decorations to DNA determine the expression of genes and thus behavior of cells. Given the advent of epigenetic clocks, measures of biological age based on characteristic age-related changes in specific sets of epigenetic marks on the genome, it is now possible to look at areas of the age-related portion of epigenetics, and declare that an individual's biochemistry appears either older or younger than the norm. Perhaps unexpectedly, supercentenarians are a mix of both.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study

Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline.

Our findings show that the epigenetic ages of Japanese centenarians and supercentenarians were remarkably lower than their chronological ages, consistently with previous findings for Italian semi-supercentenarians, suggesting that their healthy longevity has an epigenetic basis. However, whether these epigenetic ages also reflect biological age has not yet been validated. Whether healthy longevity depends on slowing epigenetic ageing or on having a younger baseline DNA methylation state would be the next subject of interest. For our multiple-sampled centenarians and supercentenarians, the longitudinal changes in epigenetic age showed that their epigenetic ageing was slower than that indirectly inferred from the cross-sectional non-centenarian cohort. Further research comparing the longitudinal epigenetic change of centenarians and supercentenarians with non-centenarians will help to answer this question.

Our study further suggests a link between the specific epigenetic states and exceptional healthy longevity in centenarians and supercentenarians. Some epigenetic signatures in centenarians and supercentenarians were maintained at young states, whereas others were maintained at advanced (or old) states. Young-state DNA-methylation signatures were overrepresented around cancer-related and neuropsychiatric disease-related genes. Conversely, CpG sites with accelerated (advanced) demethylation were also detected in centenarians and supercentenarians. Knowledge-based analyses indicated that some of these demethylated CpG sites can affect the activity of TGF-β, a major anti-inflammatory cytokine. Given that many age-related diseases can develop as a consequence of excessive pro-inflammatory responses, anti-inflammatory responses, such as those mediated by TGF-β and other cytokines, are crucial for healthy ageing and longevity. For instance, immunoassays have identified greater TGF-β activity in centenarians than in younger controls.

Autophagy is the name given to a collection of maintenance processes responsible for clearing waste and damaged proteins and structures from the cell. Autophagy is implicated in aging. It is thought to become dysfunctional and less efficient in cells in aging tissues. Further, evidence suggests that improved autophagy is an important mechanisms in the slowing of aging produced by calorie restriction and a range of other interventions tested in laboratory species. Here, researchers discuss the relationship between aging and autophagy specifically in the context of Parkinson's disease and the role of inflammatory microglia in the progression of that condition. One might compare this with a very similar paper noted last week.

In a healthy organism, the homeostasis of the central nervous system (CNS) is dependent on the interactions of various nerve cells. However, in the CNS of Parkinson's disease (PD) patients, there is an aberrant build-up of α-synuclein (α-Syn) and a cascade effect of gradual neuronal damage that breaks the appropriate balance, which leads to inflammation in the CNS. Autophagy is an evolutionarily conserved degradation pathway that is responsible for the digestion and recycling of the majority of intracytoplasmic proteins and organelles. Autophagy maintains homeostasis by delivering cytoplasmic materials to the lysosome for degradation. Due to poor autophagy, inappropriately aggregated α-Syn in the CNS of PD patients cannot be removed and accumulated. Overall, dysregulation of autophagy is thought to play an important role in the abnormal aggregation of α-Syn and the exacerbation of Parkinson's disease.

Microglia are CNS-specific immune cells that play an immunological role in the CNS comparable to that of macrophages, interact with neurons, and conduct a variety of tasks in the CNS. Recent research shows that microglial autophagy is involved in the function and regulation of inflammation in the CNS. These findings implied that dysregulation of autophagy in microglia may impact innate immune activities, including phagocytosis and inflammation, which, in turn, contribute to illnesses associated with neuroinflammation. To date, many researchers have considered PD to be a neuroinflammatory disease, and the role of microglial autophagy in the pathophysiology of PD has been a hot issue in the field. In this review, we present and highlight the contribution of microglial autophagy to the pathological mechanism of PD and aimed to determine whether microglial autophagy could be a potential target for therapeutic intervention.

Link: https://doi.org/10.3389/fnagi.2022.1039780

Researchers here review the evidence for exercise to slow the onset and progression of neurodegenerative conditions. A mountain of evidence demonstrates exercise (and the practice of calorie restriction) to improve long term health and at least modestly slow age-related degeneration. For the cost, meaning essentially free, it is a good deal. The future will bring medical technologies that can greatly improve upon the benefits of exercise by targeting the underlying causes of aging, but for now it remains one of the best options on the table.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise has a positive impact on the life quality of elderly with neurodegenerative diseases. Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics. We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.

Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.

Link: https://doi.org/10.3390/ijms24021175

The practice of calorie restriction extends life notably in short-lived mammals, but not in long-lived mammals, despite the short-term benefits to health appearing quite similar in mice and humans. This may be because many of the beneficial shifts in metabolism triggered by a low calorie intake are already built in to long-lived species, as a part of the history of evolutionary change that led to those species becoming long-lived. Since calorie restriction alters near every aspect of cellular biochemistry, coming up with a comprehensive understanding of the important mechanisms has been a slow process, never mind how those differences might then generate the large variation in effects on life span across species.

In today's open access paper, researchers apply epigenetic clocks to samples from a noted human study of calorie restriction that was conducted a while back. The clocks show little to no effect on biological age, but do suggest improvement in health that is on a par with the better lifestyle choices, such as choosing not to smoke or avoiding obesity. In the short term calorie restriction does indeed produce significant improvement in a range of markers of health related to inflammation, cardiovascular risk, and so forth. It is interesting that the presently favored epigenetic clocks are largely insensitive to this intervention.

Calorie restriction slows pace of aging in healthy adults

The CALERIE Phase-2 randomized controlled trial, funded by the US National Institute on Aging, is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the US to a 25 percent calorie-restriction or normal diet for two years. To measure biological aging in CALERIE Trial participants, the team analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.

In the primary analysis researchers focused on three measurements of the DNA methylation data, sometimes known as epigenetic clocks. The first two, the PhenoAge and GrimAge clocks, estimate biological age. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. "In contrast to the results for DunedinPace, there were no effects of intervention on other epigenetic clocks. The difference in results suggests that dynamic 'pace of aging' measures like DunedinPACE may be more sensitive to the effects of intervention than measures of static biological age." The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm), and is established to increase healthy lifespan in multiple species. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 years.

We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies, and contrasting with reports that biological aging may not be modifiable. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality.

Many more life span studies are carried out in mice rather than rats, so it is not too surprising to see people pushing the record for longest lived rat. The longest lived mice are those in which growth hormone receptor signaling is inhibited, while the longest lived rats are the result of life-long calorie restriction. The group noted here is pursuing a strategy of processing the blood plasma from young animals and then introducing the processed plasma into old animals. A treatment starting in mid-life produced a modest gain in median life span in rats, while the one still surviving rat from the small study group has surpassed the existing record for calorie restricted mice. It is an interesting data point for the field of dilution of blood plasma to reduce harmful factors present in the bloodstream of old individuals, though as I understand it, this group favors explanations involving factors from the processed young plasma that are beneficial.

Scientists working on an experimental anti-ageing therapy claim to have broken a record by extending the lifespan of a lab rat called Sima. Named after the Hindi word for "limit" or "boundary", Sima is the last remaining survivor from a group of rodents that received infusions of blood plasma taken from young animals to see if the treatment prolonged their lives. Sima, who was born on 28 February 2019, has lived for 47 months, surpassing the 45.5 months believed to be the oldest age recorded in scientific literature for a female Sprague-Dawley rat, the researchers say. So far, Sima has outlived her closest rival in the study by nearly six months.

Researchers have rushed to produce and trial therapies based on young blood plasma after numerous experiments found that infusions could reinvigorate ageing organs and tissues. The results from the latest study will be written up when Sima dies, but data gathered so far suggests that eight rats that received placebo infusions of saline lived for 34 to 38 months, while eight that received a purified and concentrated form of blood plasma, called E5, lived for 38 to 47 months. They also had improved grip strength. Rats normally live for two to three years, though a contender for the oldest ever is a brown rat that survived on a restricted calorie diet for 4.6 years.

Results from such small studies are tentative at best, but some scientists believe the work, and similar efforts by others, has potential. A preliminary study found that infusions of young blood plasma wound back the biological clock on rat liver, blood, heart and a brain region called the hypothalamus. A patent filing on the potential therapy describes how plasma from young mammals is purified and concentrated before use. Some components, such as platelets, are removed, as they can trigger immune reactions.

Link: https://www.theguardian.com/science/2023/feb/08/anti-ageing-scientists-extend-lifespan-of-oldest-living-lab-rat

Researchers here report on the results of disabling the MLKL gene involved in necroptosis, a form of programmed cell death. This reduces age-related inflammation in female mice, and delays loss of lymphocyte production in male mice. The changes are not enough to produce differences in apparent signs of aging, such as mortality rate, however. The scientific challenge here lies in linking reduced necroptosis to the observed changes in immune aging, as is usually the case in any change that is broadly related cell survival or fundamental cell activities such as replication. This sort of activity can keep research teams busy for years, but it is unclear as to whether there is a practical outcome at the end of the tunnel given that the mice didn't fare any better for the change.

MLKL is one of the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl-/- mice on a congenic C57BL/6J genetic background.

Our extensive histopathological and immunophenotypic cohort analyses have identified several unique, sex-specific, differences between congenic C57BL/6J Mlkl-/- mice and their wild-type littermates that emerge with age. Several statistically significant findings were observed in hematological parameters across age in Mlkl-/- mice compared to wild-type littermate controls. Many of these parameters remained within normal range despite statistical significance, suggesting they are unlikely to assert biologically critical roles.

Of note, Mlkl-/- mice exhibit increased circulating lymphocyte numbers relative to wild-type littermates at 12-14 months of age. A comprehensive and unbiased blind scoring of inflammatory foci in more than 44 different sites revealed a 62% decrease in background, sterile inflammation of the skeletal muscle, bone, cartilage, adipose tissue, and connective tissue proper in 17-month-old female Mlkl-/- relative to age-matched wild-type littermates. It is important to consider, however, that these differences in age-related circulating lymphocyte numbers and tissue inflammation did not manifest in any overt differences in the general condition, mobility, or mortality of these mice up to 17 months of age.

Link: https://doi.org/10.1038/s41418-023-01121-4

The evidence of recent years from studies of calorie restriction and intermittent fasting might lead one to suspect that the length of time spent being hungry is an important determining factor, on a par with calorie intake. In the course of physiological hunger, a range of signaling processes kick in and cell behavior changes in response. Is this important in distinction to the lower level nutrient sensing processes inside cells? So much changes in the course of fasting or calorie restriction that it is challenging to pick out the most relevant mechanisms.

One of the noteworthy mechanisms of hunger is ghrelin signaling. In this study, researchers stimulate the ghrelin receptor using a suitable small molecule for much of the lifespan of mice, and observe the results. The overall extension of life span is a quarter of that produced by calorie restriction, and so we might draw some conclusions from that as to the relative importance of hunger in the benefits resulting from the practice of calorie restriction or fasting. Interestingly, the short term weight gains observed in mice given this ghrelin receptor agonist in the past don't appear in this long term study, in which the controls are the heaver animals. This is possibly because the researchers didn't allow the mice to overeat, by pairing their consumption with that of the untreated control animals.

The effect of a pharmaceutical ghrelin agonist on lifespan in C57BL/6J male mice: A controlled experiment

Of the well-studied effects on lifespan in mouse models, detailed mechanisms underlying the health and longevity benefit of caloric restriction (CR) are still being investigated despite some limitations on the practical applications to humans. A major limitation of animal models is that they cannot self-report hunger or other physiological sensations that would inform mechanistic work. Since ghrelin was first described and noted as a growth hormone secretagogue receptor (GHS-R) agonist, much study has focused on the effects on hunger and appetite regulation along with other aspects of energy balance.

Investigators examining effects on cognition in mouse models have posited that the mechanism may involve interoceptive cues or signaling, rather than reduced energy intake per se. In those studies, oral administration of a ghrelin agonist (LY444711, an orally active compound that binds with high affinity to and is a potent activator of the growth hormone secretagogue receptor 1a [GHS-R1a] receptor, reduces Alzheimer's disease pathology and improves cognition in the APP-SwDI mouse model. Treatment also reduced levels of amyloid beta (Aβ) and neuroinflammation (as measured by microglial activation) at 6 months of age compared to controls, like the effect seen in the 20% CR group (gp) but with no significant difference in body weight (BW) or percentage body fat.

LY444711 binds to the human ghrelin receptor (GHS-R1a) and is a functional agonist. This agonist produced orexigenic behavior in rodents, including stimulated energy intake (food consumption is 40% than controls at 10 mg/kg and 50% greater than controls at 30 mg/kg dose), positive energy balance (23% greater BW with 2 weeks treatment at 10 mg/kg), acute higher respiratory quotient (RQ) with increased dose, and increased adiposity (greater fat mass but no significant difference in lean mass). The authors conclude this substance is orally active with an extended half-life relative to native ghrelin.

Despite various studies on ghrelin effects on food intake and body composition, studies of ghrelin agonists on lifespan-extending effects in rodent models are lacking. We tested the hypothesis that a pathway related to perceived hunger, as induced by an oral, exogenously administered orexigenic agent (i.e., a synthetic ghrelin agonist), would affect lifespan in mice. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily, animals were fed LY444711 or a placebo control until death. Treatment (GhrAg) animals were pair-fed daily based on the group mean food intake consumed by controls (ad libitum feeding) the prior week. Results indicate an increased lifespan effect for GhrAg versus controls, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue-specific mechanisms.

Microglia are innate immune cells of the central nervous system. Microglia in the aging brain respond to the age-damaged environment by becoming more activated, inflammatory, and ultimately senescent. They amplify the inflammatory environment, contributing further to damage and loss of function. One approach is to clear these cells, readily achieved using available CSF1R inhibitor drugs, after which a new population emerges that, for a time at last, is not overly activated and inflammatory. Here, researchers discuss a different approach to reducing microglial activation, without clearing the entire population of microglia, in the context of age-related blood-brain barrier dysfunction.

While it's well established that chronic mild hypoxia promotes a robust angiogenic response, we recently found that it also triggers transient blood-brain barrier (BBB) disruption, that is associated with aggregation and activation of microglia around the leaky blood vessels. Importantly, microglial depletion markedly enhanced vascular leak, demonstrating an important vasculo-protective function for microglia in maintaining BBB integrity. As a high integrity BBB is a critical determinant of cerebral health, yet evidence suggests that BBB integrity declines with age, we recently examined how aging influences both the extent of hypoxia-induced BBB disruption and the associated vasculo-protective function of microglia. This showed that compared to young (8-10 weeks) mice, the number of hypoxia-induced vascular leaks was greatly amplified (5-10 fold) in aged (20 months) mice in all regions of the brain examined.

When we analysed the impact of aging on microglia activity, we discovered an interesting paradox. On the one hand, microglia in aged brain were far more activated as assessed by morphological criteria and expression of activation markers such as Mac-1 and CD68, but on the other hand, they displayed a marked deficit in the ability to aggregate around leaky blood vessels. These findings are consistent with the work of others who showed microglia in aged brain are typically more activated than in young mice. Interestingly, microglia in the aged brain can be re-programmed by removing all microglia with the colony stimulating factor-1 receptor (CSF-1R) antagonist PLX5622, and then allowing the central nervous system to repopulate with new microglia displaying a younger phenotype. Notably, this approach was shown to reverse age-related cognitive decline, although vascular integrity was not examined.

In our study we took the simpler approach of reducing microglial activation state in the aged brain by treating mice with minocycline and this successfully reduced the number of hypoxia-induced vascular leaks. Based on these data, we proposed a biphasic relationship between microglial activation and vasculo-protection, such that microglia need to become activated to confer protection, but if they become too activated, as in the aged brain, this protection declines.

Link: https://doi.org/10.18632/aging.204509

The accumulation of senescent cells with age is an important contributing cause of age-related disease and eventual mortality. These errant cells secrete a potent mix of pro-growth, pro-inflammatory signals that disrupt normal tissue maintenance and change cell behavior for the worse, leading to structural changes and loss of organ function throughout the body. Damping senescent cell signaling, such as by selectively destroying senescent cells, has shown considerable promise as a basis for rejuvenation therapies, and the sooner that the existing approaches are widely adopted for use by the elderly population, the better.

An increase in life expectancy in developed countries has led to an insurgency of chronic aging-related diseases. In the last few decades, several studies provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype (SASP) resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers.

Strategies to prevent the pathological effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiological functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies.

Link: https://doi.org/10.1124/pharmrev.122.000622