Fight Aging! Newsletter, November 14th 2022

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  • Reprogramming to Improve Stem Cell Function Synergizes with Senescent Cell Clearance in Flies
  • Considering Mitophagy in the Aging Nervous System
  • The Still Largely Unmapped Neuroprotective Mechanisms of Exercise
  • Checkpoint Inhibition Improves Clearance of Senescent Cells
  • Evidence for Physical Fitness to Slow Loss of Cognitive Function via Lowered Blood Pressure
  • Levels of SGDG Lipids in the Brain Change with Age
  • Isochoric Cryopreservation as a Possible Path to Reversible Organ Preservation
  • Connecting IGF1 Signaling and Cellular Senescence
  • Investigating the Ability of Type 2 Diabetes Treatments to Modestly Slow Aging Extends to SGLT-2 Inhibitors
  • Aging as Instability in Dynamic Bodily Systems
  • Senescent Cells as a Cancer Vaccine
  • Is Cellular Senescence Involved in ALS?
  • Targeting the Inflammasome to Treat Parkinson's Disease
  • Soluble Phosphorylated Tau as a Target in Alzheimer's Disease and other Tauopathies
  • The Complex Vascular Contribution to Age-Related Neurodegeneration

Reprogramming to Improve Stem Cell Function Synergizes with Senescent Cell Clearance in Flies

Rejuvenation will be achieved in humans by combinations of therapies, provided periodically over time. Each individual therapy will in some way address one of the forms of cell and tissue damage that accumulate to cause the pathologies of aging. There are numerous independent sources of such damage, however. It is the case that the various types of accumulating damage, and the far greater variety of dysfunctions caused by that damage, will interact with one another to make outcomes worse than they would have been alone. Nonetheless, very different forms of rejuvenation therapy will be required to repair each of the very different forms of damage. Each individual repair therapy will produce only incremental outcomes, it will not solve all of aging.

Given this, there is, even at this comparatively early juncture in the development of rejuvenation therapies, far too little work taking place on how to best combine treatments, and on assessing the outcomes of combined treatments. Fortunately that is slowly changing, and a number of groups are at present putting earnest effort into running combinatorial studies in short-lived model organisms. Still, it is far from enough, and largely focused on metabolic adjustments that can only modestly slow aging, not repair the underlying damage.

With that in mind, today's open access paper is an interesting first step towards showing that partial reprogramming, with the effect of improving stem cell function, synergizes well with clearance of senescent cells. Both of these approaches have been shown to improve health and function in old animals, with the caveat that senolytic treatments capable of selectively destroying senescent cells are a less recent innovation, and thus come with far more data - and more robust data - demonstrating rejuvenation. The work here uses inducible expression in genetically engineered flies rather than the delivery of therapeutics into wild-type animals in order to achieve the observed results, but that is a first step towards better studies in mice.

Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan

While the number of stem cells decreases in aging animals, senescent cells accumulate with age. Manipulating cell fates by cellular reprogramming (to rejuvenate somatic cells) and by senolytic interventions (to remove senescent cells) are two promising approaches to restore homeostasis in aged individuals and to prevent age-dependent diseases. Cellular reprogramming allows differentiated cells to regain plasticity and to take on more stem cell-like qualities. A major step towards this goal was the demonstration of cellular reprogramming of terminally differentiated cells into pluripotent embryonic-like stem cell states. Such reprogramming reverses epigenetic aging marks, demonstrating that even mature, terminally differentiated cells can be returned to a younger state. While continuous expression of the Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) in mice led to the formation of teratomas and decreased lifespan, repeated short term expression in adult mice succeeded in ameliorating cellular and physiological signs of aging. Subsequently, several studies have suggested that this approach can be applied to human aging and age-related disease, and cycling expression can rejuvenate stem cells in vitro.

Ablation of senescent cells has been shown to reverse tissue dysfunction and extend healthspan in mice. A recent study using a senolytic construct (FOXO4-DRI peptide) that induced apoptosis in senescent cells, by interfering with the binding of p53 to FOXO4 thereby freeing p53 to activate apoptosis, showed that the clearing of senescent cells both counteracted senescent cell induced chemotoxicity and restored age-dependent declines in physical performance, fur density, and renal function in aging mice. Several studies have further explored applications of different senolytic strategies to ameliorate age-related decline and disease.

Accumulation of senescent cells and loss of stem cells are not independent processes. Through the senescence-associated secretory phenotype (SASP), senescent cells release pro-inflammatory cytokines which contribute to chronic inflammation and mTOR activation, ultimately leading to stem cell exhaustion. This interaction suggests that senolytic therapies might interact with cellular reprogramming strategies in delaying age-dependent decline and disease. We have previously explored drug-drug interactions as synergistic aging interventions, and here we ask whether a combinatorial treatment of OKSM and senolytic (Sen) expression could mitigate or reverse the effects of aging more efficiently than either intervention alone.

To test this hypothesis, we induced expression of OKSM, Sen, and an OKSM-Sen combination in adult flies and compared their effects on health and lifespan. We find that each treatment alone had limited benefits, with OKSM alone benefiting maximum lifespan while Sen expression alone increased mean lifespan but had no effect on maximum lifespan. In contrast, animals subjected to the combined intervention experienced substantially longer mean and maximum lifespan. Our data is consistent with a synergistic interaction between the two interventions, simultaneously rejuvenating stem cells and removing senescent cells.

Considering Mitophagy in the Aging Nervous System

Mitophagy is the selective version of autophagy focused on recycling mitochondria. Every cell contains hundreds of mitochondria, their primary responsibility the generation of chemical energy store molecules to power cellular processes. Mitochondria are the descendants of ancient symbiotic bacteria. They lead dynamic lives, replicating like bacteria, passing component parts around, and fusing together. Mitophagy is a quality control mechanism, removing damaged mitochondria in order to prevent cellular dysfunction. A good deal of evidence suggests that age-related declines in mitochondrial function are in large part caused by a progressive failure of the operation of mitophagy.

Like the general processes of autophagy, mitophagy is thought to decline in efficiency with age. This can result from reasons peculiar to the involvement of mitochondria, such as changes in their dynamics that lead to greater resistance to mitophagy, or to defects in the common mechanisms of autophagy, such as formation or transport of autophagosomes, or defects in the function of the lysosomes responsible for breaking down cellular waste. It isn't always completely clear that specific metrics of autophagy are relevant in every tissue, or that autophagy is declines with age in all tissues, however. Too much autophagy can cause as much harm as too little autophagy, but a raised level of a specific autophagy-associated protein might in fact indicate a breakage in later portions of the autophagic process, rather than greater autophagy per se. Other ambiguities attend the various means of assessing autophagy. It is an area of research that still requires considerable work aimed at improving fundamental understanding.

Mitophagy in the aging nervous system

Living longer is changing our global population, with major ramifications for brain health and cognition. Why some humans experience accelerated neural aging compared to others remains to be fully understood. Autophagy and mitophagy are pathways of outstanding clinical interest with major relevance for neural integrity because human neural function depends upon quality control over a timespan of decades. Although mitophagy levels decline in short-lived model organisms, it remains unclear if decreased levels of mitophagy are a hallmark of all cell types during natural aging in the mammalian nervous system. Furthermore, it remains unclear if certain cerebral regions and cellular subtypes exhibit greater susceptibility to age-related changes than others. For example, cortical thickness is a widely used metric in human aging studies but the first large-scale heterochronic datasets (brain charts) are only beginning to emerge. Delineating the regional and cell subset-specific regulation of mitophagy will be critical to develop neuroprotective interventions that might improve healthspan or even reverse human age-related degeneration.

It will also be exciting to discover the possible interplay between emerging mitophagy pathways, and age-dependent pathology in the mammalian nervous system. Crosstalk between basal mitophagy and other mitochondrial responses e.g., outer membrane remodeling in response to infection and signalling or degradative mitochondria-derived vesicle (MDV) formation also represent intriguing avenues for future investigation. Whether elevated levels of mitophagy are beneficial for neural integrity also remains a mystery. What is the "minimum effective threshold" of basal mitophagy or macroautophagy required to safeguard neural integrity? How can we control or fine tune mitophagy to prevent a deleterious outcome? What is the relationship between physiological mitophagy and contemporary concepts in geroscience, such as epigenetic aging? The continued development and characterisation of novel tools presents a unique opportunity to resolve these longstanding questions.

What is the role of selective autophagy in the neuroprotective effects afforded by behavioral interventions? There are clear pro-longevity effects of exercise for cognitive, cerebrovascular, and systemic health. Indeed, autophagy and mitophagy are impacted by exercise in different model systems. Developing robust protocols and pharmacological strategies to augment selective autophagy pathways in humans represents a major challenge, because we do not have rapid, non-invasive assays that can reliably monitor distinct forms of autophagy in the clinic (at point of care). Equally, such clinical assays would need to distinguish between the degradative and signalling functions of autophagy (not a trivial task, even under laboratory conditions). Moreover, it remains unknown if changes in serum levels of autophagy markers reflect alterations in cell or tissue-specific autophagy pathways. These are challenging questions, but also exciting opportunities that will lead to a better understanding of physiological mitophagy in tissue development, disease and repair.

The Still Largely Unmapped Neuroprotective Mechanisms of Exercise

Regular moderate exercise delays the onset of neurodegeneration in late life. Since exercise produces sweeping changes throughout the body and the operation of cellular metabolism. It is easy enough to look at what is known of the connections to brain aging, such as a reduction in the chronic inflammation associated with aging, or upregulation of beneficial metabolites leading to an increase in BDNF expression and consequent neurogenesis, and say that these are the most important factors. But one suspects that any number of other relevant mechanisms may remain to be discovered and characterized, and since researchers don't have a good grasp on the relative importance of the known mechanisms, those unknown mechanisms could well account for a sizable fraction of the outcome.

Regardless, the difference in late life health between highly active hunter-gatherer populations and largely inactive populations in wealthier regions of the world is sizable. This is particularly true for cardiovascular disease, but also applies to much of the panoply of common conditions that afflict older people. Degree of life-long exercise is likely a primary contributing factor in that difference. Given that we know that exercise is one of the safest forms of intervention, not to mention one of the cheapest, it seems self-sabotaging not to undertake more of it.

New insights into how exercise protects against neurodegenerative diseases

Accumulating evidence finds that exercise can improve brain function and delay or prevent the onset of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. While the underlying mechanisms remain unclear, recent research suggests that exercise-induced activation of peripheral systems such as muscle, gut, liver, and adipose tissue may affect neural plasticity. Cathepsin B (CTSB), a myokine, and brain-derived neurotrophic factor (BNDF) have been found to possess robust neuroprotective effects.

In a new study, investigators looked at whether increasing aerobic exercise intensity would increase the amount of CTSB and BDNF circulating in the blood. Sixteen young healthy subjects completed treadmill-based aerobic exercise at maximum capacity and then at 40%, 60%, and 80% of capacity. Circulating CTSB and BDNF were measured in blood samples taken after each bout of exercise, and CTSB protein, BDNF protein, and mRNA expression were measured in skeletal muscle tissue. Researchers found that high intensity exercise elevates circulating CTSB in young adults immediately after exercise, and that skeletal muscle tissue expresses both message and protein of CTSB and BDNF.

Further, new review articles cover interorgan crosstalk between muscle, liver, adipose tissue, the gut microbiome, and the brain. While it is well known that exercise protects the central nervous system, it has only recently been found to depend on the endocrine capacity of skeletal muscle. Researchers highlight the impact of myokines, metabolites, and other unconventional factors that mediate effects of muscle-brain and muscle-retina communication on neurogenesis, neurotransmitter synthesis, proteostasis, mood, sleep, cognitive function and feeding behavior following exercise.

They also raise the possibility that detrimental myokines resulting from inactivity and muscle disease states could become a novel focus for therapeutic intervention. "We propose that tailoring muscle-to-central nervous system signaling by modulating myokines and metabolites may combat age-related neurodegeneration and brain diseases that are influenced by system signals."

Checkpoint Inhibition Improves Clearance of Senescent Cells

Immune checkpoint inhibition, such as via targeting PD1, is used to fire up the immune system to attack cancer, temporarily disabling some of the natural mechanisms intended to prevent immune cells from running amok. In the case of cancer, this is intended to overcome the abuse of immune checkpoints by cancerous tissue, one of the many strategies by which an established tumor suppresses or co-opts the immune system. But does inhibition of immune checkpoints improve other aspects of immune function? Apparently so, as in today's open access paper, researchers present evidence for a reduced burden of senescent cells following checkpoint inhibition.

Interestingly, it is unclear as to whether the improvement of measures of health in mice is as much a matter of reducing the harmful pro-inflammatory senescence-associated secretory phenotype (SASP) as it is resulting from clearance of senescent cells. Checkpoint inhibitors, at least PD-L1, appear to be involved in generation of the SASP, as cells lacking that gene produce a more muted SASP.

While this is interesting research, checkpoint inhibition seems unlikely to be a viable addition to the range of senolytic therapies presently under development, however. If one looks at the clinical trial data for established checkpoint inhibitors used to treat cancer, there appears to be something like a 7% chance of lasting complications resulting from treatment. That list of problems includes the possibility of developing forms of autoimmunity - immune checkpoints exist for a reason. The cost-benefit equation for a cancer that will go on to kill you, and for which the alternative treatments are worse, is somewhat different to that for an increased burden of senescent cells that will kill you very much more slowly, and for which the range of alternative treatments come with next to no risk of lasting side-effects.

Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP).

Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes.

These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.

Evidence for Physical Fitness to Slow Loss of Cognitive Function via Lowered Blood Pressure

As is true of excess weight, the raised blood pressure appears to have a lower threshold for causing long-term harm to health than is commonly thought. Negative effects increase as blood pressure increases, but the point at which harms start is surprisingly close to normal blood pressure ranges. More aggressive control of blood pressure via antihypertensive drugs and lifestyle changes produces benefits even when pushing it back down into what the normal range. The boundary at which raised systolic blood pressure is considered to be a problem, veering into the territory of hypertension, was recently lowered by ten points.

There are any number of mechanisms by which raised blood pressure causes harm. It accelerates the onset and progression of atherosclerosis. It increases the pace at which small blood vessels rupture in the brain, where neural tissue is not effectively repaired once so damaged. It helps to disrupt the blood-brain barrier and other aspects of endothelial function. Thus it isn't to surprising to note the correlations between blood pressure and later life cognitive function, and between lifestyle choices that affect blood pressure and later life cognitive function, as in today's open access paper.

Mean arterial pressure, fitness, and executive function in middle age and older adults

Physical activity and associated gains in fitness have been shown to be neuroprotective for older adults, with evidence suggesting preserved brain structure, function, and better cognitive functioning. Many recent meta-analyses suggest that exercise interventions and subsequent gains in fitness may have a selective effect on cognition in older adulthood, with the greatest impact on executive functioning. Some evidence suggests that changes in executive function may be occurring earlier in middle age and may be predictive of future cognitive decline. Therefore, there is a need to examine how fitness may be related to executive function across a younger adult sample.

Cardiorespiratory fitness (CRF) is a measure of the ability of the circulatory and respiratory systems to deliver oxygen, and the peak rate at which oxygen can be consumed, during sustained physical activity at a maximal effort. Higher CRF has been shown to be related to greater brain volume, particularly in gray matter regions like the prefrontal cortex. Higher CRF has also been associated with preserved white matter integrity, and functional connectivity, as well as better cognitive functioning in older adults. However, the mechanisms underlying these positive effects are not fully understood.

The purpose of the current study was to examine whether mean arterial pressure (MAP) mediated the association between CRF and executive function in middle age and older adults. Participants were adults (age 40+) without any self-reported psychiatric and neurological disorders or cognitive impairment from the Nathan Kline Institute Rockland Sample (N = 224, M age = 56). CRF was defined by V̇O2max estimated via a bike test, neuropsychological testing was used to examine executive functioning, and MAP was calculated from systolic and diastolic blood pressure recordings. Mediation models were analyzed controlling for age, sex, and education.

Results indicated that higher CRF was associated with better inhibition and there was a significant indirect effect of greater CRF on better inhibition through lower MAP. There were additional significant indirect effects of greater CRF and better fluency and planning through lower MAP. This suggests that MAP may be an underlying physiological mechanism by which CRF influences executive function in mid- and older adulthood.

Levels of SGDG Lipids in the Brain Change with Age

Researchers here note one aspect of many in the changing landscape of lipids in the aging brain. Like all such discoveries, it is initially hard to say where it stands in the complex web of cause and consequence that is degenerative aging. Aging is made up of many layers of cause and effect, leading from fundamental causes of aging, good targets for therapies that might alleviate a broad range of age-related conditions, to far downstream consequences of consequences of consequences that would have only a narrow, limited positive impact on health if targeted for restoration.

3-sulfogalactosyl diacylglycerols (SGDGs) are a class of lipids, also called fats. Lipids contribute to the structure, development, and function of healthy brains, while badly regulated lipids are linked to aging and diseased brains. However, lipids, unlike genes and proteins, are not well understood and have often been overlooked in aging research. Researchers recently made three discoveries involving SGDGs: In the brain, lipid levels are very different in older mice than in younger mice; all SGDG family members and related lipids change significantly with age; and SGDGs may be regulated by processes that are known to regulate aging.

"SGDGs were first identified in the 1970s, but there were few follow-up studies. These lipids were essentially forgotten and missing from the lipid databases. Nobody knew SGDGs would be changing or regulated in aging, let alone that they have bioactivity and, possibly, be therapeutically targetable." The analysis showed that SGDGs possess anti-inflammatory properties, which could have implications for neurodegenerative disorders and other neurological conditions that involve increased inflammation in the brain. The team also discovered that SGDGs exist in human and primate brains, suggesting that SGDGs may play an important role in animals other than mice. Further research will be required to show if SGDGs contribute to human neuroinflammation.

Isochoric Cryopreservation as a Possible Path to Reversible Organ Preservation

An important goal in cryopreservation research is to find an efficient way to reversibly cryopreserve whole organs and then larger masses without ice crystal formation and other structural damage, leading up to whole body preservation. Being able to take donated organs and provide them with an indefinite shelf life would revolutionize the logistics of the transplant industry. Later, it would enable an efficient industry for manufacture of new organs, as tissue engineering capabilities increase. The eventual goal for this technological capability is to greatly improve the ability to preserve individuals at clinical death, maintaining them in cold storage indefinitely, with minimal additional damage, until technological progress allows for repair and revival.

The start of the modern field of cryobiology is thought to have happened in 1948, with the discovery of the cryoprotective effects of glycerol, a cryoprotective agent (CPA) that prevents ice crystal formation through the creation of bonds with free water molecules. Since then, a huge aspect of cryobiology and cryopreservation technologies was that we can modulate a given system's chemistry by involving CPAs, which could, in theory, allow us to preserve a live biologic sample for a long time. Many more CPAs, like dimethyl sulfoxide (DMSO), appeared on the scene afterwards, revolutionizing the subfield of human sperm cryopreservation. In 1972, scientists published evidence of the first-ever successful cryopreservation of mammalian embryos using slow-freezing. Eleven years later, the first-ever human embryo was cryopreserved.

A turning point in cryobiology happened in the 1980s, the so-called golden era of cryopreservation. Researchers introduced the process of vitrification to medical cryopreservation. Vitrification is a process of rapid cooling of liquid medium until it becomes a glass-like non-crystalline amorphous solid. It requires the protective effect of CPAs, which lower the freezing point of water, as a major part of biological systems. In its vitrified state, water is locked in place, preventing the formation of ice crystals, and the entire sample becomes a glass-like solid. Vitrification is used widely today in the cryopreservation of very small biological samples (specifically in in vitro fertilization and other reproductive applications), and many cryobiologists believe it could eventually be applied to freeze any biological materials, even organs and whole organisms.

One of the major focus in cryobiology research is, in fact, centered around the process of vitrification and how much and which CPAs to add during this stage, or how to remove these often toxic compounds in the rewarming stages. But, so far, CPA-aided vitrification only enabled the routine preservation of cells and cell suspensions and failed to produce any clinically translatable technique on how to reversibly preserve any complex biological systems like organs outside of the human body.

Methods in cryopreservation haven't changed much in the last few years but there is a different approach currently available called isochoric cryopreservation. The term stands for cryopreservation of biological tissues at a constant volume, versus the more "traditional" way of cryopreservation that's done at constant pressure, called isobaric cryopreservation. During isochoric preservation, the cooling process happens in a confined, constant-volume chamber, representing one of the biggest differences between isochoric and isobaric conditions. Another difference is minimized role of CPAs, which are very much needed in the classical isobaric cryopreservation, but not in several modes of isochoric cryopreservation.

The advantage of isochoric freezing is that it completely avoids the question of the toxicity associated with CPA usage as well as the amount of CPAs needed to be present in the biological sample you might want to freeze. Even if there is a need to use CPAs, their concentrations would be dramatically decreased. Under isochoric conditions, a biological sample is confined within a container with high rigidity and strength, usually made out of titanium. The container is completely absent of the bulk gas phase, and is denied any access to the atmosphere, which changes both the thermodynamic equilibrium and the ice nucleation kinetics within the system inside.

Connecting IGF1 Signaling and Cellular Senescence

It is satisfying to see long-standing areas of metabolism-focused aging research find connections to forms of cell and tissue damage thought to drive aging. A great deal of effort has gone towards characterizing growth hormone and IGF1 signaling in aging, as manipulating this part of cellular metabolism has been shown to slow aging in mice. The human population with loss of function in growth hormone receptor, producing Laron syndrome, is the subject of analogous studies. Here, researchers report on evidence for IGF1 stimulation to produce a greater burden of cellular senescence, a possibly important mechanism to explain why reduced IGF1 signaling can slow aging in laboratory animals. Senescent cells, when they linger in increasing numbers with age, produce inflammatory signaling that actively harms tissue structure and function.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth, and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to very low endogenous IGF1 levels in LS is associated with small stature as well as endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer.

Studies conducted on LS-derived cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis.

In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.

Investigating the Ability of Type 2 Diabetes Treatments to Modestly Slow Aging Extends to SGLT-2 Inhibitors

There is something of a trend towards picking over the landscape of type 2 diabetes medication in search of therapies that can modestly slow aging, at least in animal models. If metformin is anything to go by, we shouldn't be at all optimistic that this will result in useful outcomes in humans. "Useful" in this context means reliable gains in late life health and life expectancy in metabolically normal people, where those gains are larger than those that can be achieved with exercise, and with minimal side-effects. Otherwise, this seems like time and effort that could be directed to more productive areas of research and development.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence.

Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1) animal models of healthspan and lifespan; 2) selected molecular pillars of aging in preclinical models; 3) biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

Aging as Instability in Dynamic Bodily Systems

Here find an interesting view of aging as the evolution of a complex dynamic system, at the point of criticality between stability and instability, towards a lesser ability to recover from perturbations. Eventually the usual small day to day changes that occur throughout life, to the environment, to exposure to stresses, to the normal operation of biological systems, will push an old organism into catastrophic failure, where a young organism would easily recover.

Aging is a very slow process that occurs at characteristic time scales far exceeding times associated with molecular processes or operations of an organism's functional subsystems. Typically, such a hierarchy of scales arises from criticality, which is a special case of a dynamic system operating close to a tipping point separating the stable and unstable region. We proposed that aging results from inherent dynamic instability of the underlying regulatory networks and manifests itself as small deviations of the organism state variables (physiological indices) get exponentially amplified and lead to the exponential acceleration of mortality. The first principal component score is then an approximation to the order parameter characterizing the unstable phase and having the meaning of the total number of regulatory errors accumulated in the course of life of the animal. Hence, we believe that aging at criticality conjecture provides a good explanation for the success of Principal Components Analysis (PCA) as a semi-quantitative tool in aging research.

However, the abilities of linear rank reduction techniques, such as PCA, to unravel an accurate dynamic description of aging are limited for the following reasons. First, there are no reasons to believe that the effects of non-linear interactions between different dynamic subsystems are small. That is why a biomarker produced from such a linear analysis cannot be expected to perform well in different biological contexts. To compensate for the drawbacks of PCA, we combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements. Assuming that aging results from a dynamic instability of the organism state, we designed a deep artificial neural network, including auto-encoder and auto-regression (AR) components. The AR model tied the dynamics of physiological state with the stochastic evolution of a single variable, the "dynamic frailty indicator" (dFI). In a subset of blood tests from the Mouse Phenome Database, dFI increased exponentially and predicted the remaining lifespan.

Senescent Cells as a Cancer Vaccine

Researchers here note the discovery that vaccinating mice with senescent cancer cells ensures that the immune system will more aggressively attack a later introduction of cancerous cells. Since we know that most cancer therapies induce senescence in cancerous cells to a fair degree, one has to think that the effectiveness of this approach will diminish as a cancer progresses to form a solid tumor and co-opts the immune system in various ways. Still, it sounds as though it could be a potentially useful after, for example, surgical resection of a tumor, to help reduce the odds that the cancer will reoccur.

Scientists have studied how inducing senescence in cancer cells improves the effectiveness of the immune response to a greater degree than the dead cancer cells. After vaccinating healthy mice with senescent cancer cells and then stimulating the formation of tumours, the researchers observed that the animals did not develop cancer or that the number that do is significantly reduced. They also analysed the efficacy of vaccination in animals that had already developed tumours. In this setting, although the results were more moderate due to the protective barrier of the tumour, improvements were also observed.

The researchers tested the technique in animal models of melanoma, a type of cancer characterised by high activation of the immune system, and also in pancreatic cancer models, which present strong barriers against immune cells. Prophylactic vaccination therapy with senescent cancer cells was effective against both types of tumors. They also complemented the study with tumour samples from cancer patients and confirmed that human cancer cells also have a greater capacity to activate the immune system when they are previously rendered senescent. The group is now studying the combined efficacy of vaccination with senescent cells and immunotherapy treatments.

Is Cellular Senescence Involved in ALS?

Amyotrophic lateral sclerosis (ALS) is not an age-related condition per se, but most cases do occur in later life. Is this because one or more mechanisms of aging are relevant to the onset of ALS? Researchers here argue for cellular senescence to be involved. It is already the case that cellular senescence has been implicated in a broad range of conditions, not all of which are age-related, such as type 1 diabetes. The advent of effective senolytic therapies to clear senescent cells from tissues will benefit more than just aged people.

Our unbiased proteomic analysis of plasma and peripheral blood mononuclear cells (PBMCs) in blood samples from patients with ALS has shown the activation of molecular pathways involved in immunoregulation and cell senescence in faster progressing ALS and at a later stage of disease. We and others have also reported an increased blood and cerebrospinal fluid concentration of proinflammatory cytokines in individuals with ALS. These inflammatory mediators are enumerated within the senescence-associated secretory phenotype (SASP) and have been described in age-related immune dysregulation.

The SASP inflammatory microenvironment spreads the tissue-disrupting effect of senescence regionally and systemically, impairing the function of other immune cells. Critically, other alterations observed in aging and senescence are aligned with brain-specific changes seen in ALS, including a disturbed autophagy/lysosomal protein degradation, altered RNA splicing, and errors in nuclear-cytoplasmic transport. We can therefore hypothesize a potential role for cell senescence in the immunologic dysregulation identified in ALS.

In this study, we used a two-stage approach to first investigate the immunophenotype of PBMCs from individuals living with ALS and then focused on lymphocytes expressing known features of immunosenescence. We showed that lymphocytes from patients with ALS are skewed toward a senescent and late memory state when compared with those from age-matched healthy controls.

Targeting the Inflammasome to Treat Parkinson's Disease

Neurodegenerative conditions, such as Parkinson's disease, are strongly connected to chronic inflammation of brain tissue. Unresolved inflammation is disruptive to tissue function in many ways, and the immune cells of the brain are tightly integrated into the normal functioning of neurons and their synaptic connections. It is thus an important goal for the research community to find ways to suppress excessive, unresolved inflammation without also disrupting the necessary inflammatory signaling that is required for health and the normal operation of the immune system. Early immunomodulatory treatments are blunt tools, usually targeting a single signal molecule involved in inflammation, and can cause long term harm via suppression of the normal immune response. It is hoped that the inflammasome and its role in the regulation of inflammation will prove to be a better target.

Parkinson's disease (PD) is the second-most common neurodegenerative disease, predominantly affecting the elderly. The pathogenesis of PD contributed by both environmental and genetic factors is rather complex and not fully understood. The limited treatment options also add to its socioeconomic impact. Importantly, to date, no therapies are able to prevent or delay the disease progression. Thus, there is an enormous need to have a deeper understanding of PD pathogenesis and develop novel therapeutic approaches to improve the lives of PD patients.

Among the various novel approaches to manage PD, immunomodulation has gained much popularity recently. This approach is conceived based on the heavy involvement of the immune system in the pathogenesis and progression of PD. Neuroinflammation is one of the immune processes of paramount importance in PD. Reactive microglia increased significantly in the substantia nigra region of PD patients upon post-mortem examinations. Moreover, enhanced microglial activation was also observed in various PD animal models. Besides central nervous system (CNS) inflammation, peripheral inflammation is also believed to play a pivotal role in PD. Peripheral pro-inflammatory stimuli can be transported to the brain, activate the primed microglia, prompt neuroinflammation, and exacerbate disease progression.

An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.

Soluble Phosphorylated Tau as a Target in Alzheimer's Disease and other Tauopathies

The primary thrust of Alzheimer's research and clinical development of therapies remains the targeting of amyloid-β and tau aggregates. The failure to produce meaningful benefits in patients, even given reductions in amyloid-β and tau, is not shifting the focus of most research groups to other entirely different approaches, but rather to question whether the complexity of amyloid-β and tau biochemistry means that the wrong locations or types of these molecules were targeted by the immunotherapies used to date in human trials.

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum.

Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble cerebrospinal fluid (CSF) p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates.

Our data suggests that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

The Complex Vascular Contribution to Age-Related Neurodegeneration

Vascular issues arguable precede the protein aggregates and other noted signs of neurodegenerative conditions. The brain is an energy-hungry organ, and the nutrients and oxygen to fuel it arrive via blood flow through the vasculature. Parts of the brain already operate at the edge of capacity, as illustrated by the ability of exercise to rapidly improve neural function such as memory for a short period of time, due to increased blood flow. The decline of the vasculature with age impairs the brain in a range of different ways, not just a reduced supply of nutrients, but also leakage of the blood brain barrier to provoke inflammation, as well as other issues.

Vascular contributions to cognitive impairment and dementia (VCID) is a complex syndrome that encompass a diverse array of pathologies resulting in disruptions of blood flow in the brain. It is becoming increasingly recognized that VCID is one of the leading causes of dementia along with Alzheimer's disease (AD) and is frequently found co-morbid with AD pathologies. Experts project a significant increase in the number of patients presenting with both cerebrovascular and neurodegenerative co-morbidities as the number of persons living into their 80s and 90s increases. Recent studies have even demonstrated pathologic vascular changes precede the appearance of amyloid (Aβ) plaques and neurofibrillary tangles, characteristic proteinopathies associated with AD, further implicating cerebrovasculature pathologies as an important topic of study in the fields of dementia and neurodegeneration.

The overlap between VCID and AD continues when considering significant risk factors associated with their disease progressions. Hypertension, diabetes, hyperhomocysteinemia (HHCy) and hyperlipidemia are risk factors for both AD and VCID all leading to a state of both chronic neuroinflammation and chronic cerebral hypoperfusion or hypoxia. Neuroinflammation is both an important instigator and consequence of cerebrovascular pathology making this an important potential therapeutic target for impeding disease progression. While there is currently no cure for VCID, several studies have been focused on mitigating the aforementioned risk factors leading to chronic hypoxia and inhibiting the subsequent neuroinflammatory sequalae.

In the following review a brief overview of the current knowledge surrounding VCID will be provided with a focus on the basic mechanisms linking well-established risk factors with the distinct signaling cascades of neuroinflammation and chronic hypoperfusion. Then the coalescence of these two pathologic signaling cascades and their synergistic impact on the downstream activation of further neurodegenerative sequalae will be discussed. Finally, several potential therapeutic interventions to target specific aspects of the degenerative cascade leading to VCID progression will be highlighted.

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