Fight Aging! Newsletter, December 5th 2022

A large body of work, carried out over the past decades in a range of model organisms including yeast, worms, flies and mice, has identified hundreds of genetic variants as well as numerous dietary factors, pharmacological treatments, and other environmental variables that can increase the length of life in animals. Current concepts regarding the biology of aging4 are in large part based on results from these lifespan studies. Much fewer data, however, are available to address the question of whether these factors, besides extending lifespan, in fact also slow aging, particularly in the context of mammalian models.

It is important to distinguish lifespan vs. aging because it is well known that lifespan can be restricted by specific sets of pathologies associated with old age, rather than being directly limited by a general decline in physiological systems. In various rodent species, for instance, the natural end of life is frequently due to the development of lethal neoplastic disorders: Cancers have been shown to account for ca. 70-90% of natural age-related deaths in a range of mouse strains. Accordingly, there is a strong need to study aging more directly, rather than to rely on lifespan as the sole proxy measure for aging.

Deep phenotyping represents a powerful approach to capture a wide range of aging-associated phenotypic changes, since it takes into account alterations at molecular, cellular, physiological, and pathological levels of analysis, thereby providing a very fine-grained view of the consequences of aging as they develop across tissues and organs. The approach is therefore ideally suited to assess genetic variants, pathways, dietary or pharmacological factors previously linked to lifespan extension and, potentially, delayed aging. Deep phenotyping examines hundreds of parameters, many of which are expected to differ between young and old animals (hereafter called age-sensitive phenotypes; ASPs); these can be collectively used to address if and how a given intervention interacts with the biological processes underlying the signs and symptoms of aging.

We here refer to the mechanisms of aging as the sets of processes that underlie age-dependent phenotypic change. Accordingly, an intervention that targets the mechanisms underlying aging should slow the transformation of a phenotypically young to a phenotypically aged organism. In other words, the intervention should attenuate the age-dependent change in ASPs (the delta in phenotype between young and old). For instance, a specific intervention or genotype could ameliorate the age-dependent loss of neurons by promoting processes concerned with maintaining the integrity of neurons over time.

An intervention could mimic a targeting of age-dependent change by affecting ASPs directly (i.e., independently of age-dependent change in these phenotypes). For instance, a specific genetic variant may increase the number of neurons by promoting neurogenesis during brain development, without affecting the rate of subsequent age-dependent neuron loss. This variant would regulate neurodevelopmental processes but would not affect the mechanisms underlying age-dependent change. Although this would also result in increased neuronal numbers in old age, it cannot be taken as evidence of a slowed progression of aging because the rate of age-dependent change remains unaltered

Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. To cover key genetic longevity interventions and study their effects on aging in mice, we here chose genetic models targeting the mTOR pathway as well as growth hormone signaling. In parallel to our studies in mice, we applied multi-dimensional phenotyping combined with stratification based on genetic expression variants in GHRHR and MTOR in a human population across a wide age range, spanning from 30 to 95 years. The analyses in humans complement our work in animal models and allowed us to address, in parallel to the work in mice, whether or not a potential genetic modification of human ASPs occurs in an age-independent fashion or not.

We examine these key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Contrary to a general expectation that 'anti-aging' treatments should produce a broad change in aging rate across many phenotypes, our study shows that the PAAIs we examined - that are concerned with some of the very core mechanisms proposed to be involved in aging - often did not seem to work through targeting age-dependent change.

In conclusion, the PAAIs examined (i.e. mTOR loss of function, Ghrhr loss of function, intermittent fasting-based version of dietary restriction) often influenced age-sensitive traits in a direct way and not by slowing age-dependent change. Previous studies often failed to include young animals subjected to PAAI to account for age-independent PAAI effects. However, any study not accounting for such age-independent intervention effects will be prone to overestimate the extent to which an intervention delays the effects of aging on the phenotypes studied. This can result in a considerable bias of our view on how modifiable aging-related changes are.

Age - it's the one mountain you can't overcome, and as the average life expectancy extends into the eighth decade, neurodegenerative diseases are becoming increasingly prevalent. Despite their increasing incidence, preventative or disease-modifying strategies for these emotionally and financially draining disorders are lacking. Due to the fundamental lack of regeneration within the central nervous system (CNS), neurodegenerative diseases that relentlessly attack discrete populations of neurons are excellent candidates for cell replacement therapies. Here, we review the current prospects on the application of pluripotent stem cell-derived cell types for the treatment of neurodegenerative disease.

Pluripotent stem cells provide a uniquely scalable source of functional somatic cells, including cells of the CNS, that can potentially replace damaged or diseased tissues. Although prospects for using stem cell derivatives seemed fanciful at the start of the millennium, approximately two decades later several clinical trials using cellular products of pluripotent stem cells are underway or about to reach the clinic. It's an incredibly exciting time for stem cell-based regenerative medicine with a number of clinical trials started and more just on the horizon for neurodegenerative diseases, including one for Parkinson's disease.

The demand for neurodegenerative disease therapeutics continues to grow as populations around the globe age. Currently, no pharmacological strategies exist that can significantly alter disease course for neurodegenerative diseases, thus cell replacement therapies remain an attractive avenue of exploration. Although the prospect of using stem cell-derived neurons to treat many of the diseases discussed in this review remains abstract, the Parkinson's disease clinical trials, grounded on years of fetal transplant studies and animal models with high fidelity, will provide important guideposts as others venture into these uncharted territories.

As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota axis, which is a bidirectional link between the gastrointestinal tract and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia.

A substantial amount of research has been conducted on the role and abundance of the intestinal microbiome as well as the implications for maintaining a healthy state. Gut microbiota is an ecosystem metabolic of a million different microorganisms living in the gastrointestinal tract and forming a symbiotic connection with the host. Because the gut microbiota helps to maintain physiological homeostasis, alterations in microbiome abundance taxa cause intestinal dysbiosis related to numerous pathological conditions, including neurodegenerative diseases. Thus, microbiota-based therapies emerge as a potential therapeutic target, including prebiotic or probiotic administration, nutrition, and physical activity to reshape the gut microbiota.

Here, we review the role of the gut microbiome in aging and neurodegenerative diseases, as well as provide a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.

Advancements in medicine have increased the longevity of humans, resulting in a higher incidence of chronic diseases. Due to the rise in the elderly population, age-dependent neurodegenerative disorders are becoming increasingly prevalent. The available treatment options only provide symptomatic relief and do not cure the underlying cause of the disease. Therefore, it has become imperative to discover new markers and therapies to modulate the course of disease progression and develop better treatment options for the affected individuals. Growing evidence indicates that neuroinflammation is a common factor and one of the main inducers of neuronal damage and degeneration.

This review focuses on summarizing the immune-regulatory activities of three predominant members of the galectin (Gal) family - Gal-1, Gal-3, and Gal-9 - which are known to play a significant role in neurodegenerative ailments. Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) display similar characteristics, including native protein accumulation, neuronal degeneration, and cognitive and behavioral impairment.

Gal-1 mRNA and protein levels have been shown to be higher in the spinal cords of SOD1 mice displaying phenotypes similar to ALS in humans. In addition, higher mRNA and protein expression of Gal-3 and Gal-9 has been observed in the spinal cords of SOD1 mice and sporadic ALS patients. Gal-3 specifically has been identified as a biomarker in serum, plasma, and/or cerebrospinal fluid (CSF) in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). It has also shown detrimental regulation of inflammatory responses in AD. Further, moderate cognitive impairment in AD has been associated with Gal-9.

This information suggests that targeting Gals has a promising therapeutic potential to treat inflammatory and neurodegenerative disorders. In this review, we discuss the role of Gals in the causation and progression of neurodegenerative disorders. We describe the role of Gals in microglia and astrocyte modulation, along with their pro- and anti-inflammatory functions. In addition, we discuss the potential use of Gals as a novel therapeutic target for neuroinflammation and restoring tissue damage in neurodegenerative diseases.

Vascular smooth muscle cells (VSMCs) are the most abundant cell in vessels. Earlier experiments have found that VSMCs possess high plasticity. Vascular injury stimulates VSMCs to switch into a dedifferentiated type, also known as synthetic VSMCs, with a high migration and proliferation capacity for repairing vascular injury. In recent years, largely owing to rapid technological advances in single-cell sequencing and cell-lineage tracing techniques, multiple VSMCs phenotypes have been uncovered in vascular aging, atherosclerosis, aortic aneurysm, etc. These VSMCs all down-regulate contractile proteins such as α-SMA and calponin1, and obtain specific markers and similar cellular functions of osteoblast, fibroblast, macrophage, and mesenchymal cells.

The synthetic VSMCs are considered as the de-differentiated state of contractile VSMCs, accompanied by morphologic changes from spindle shape to irregular shape. With the decrease of contractile protein expression, the proliferation and migration ability of synthetic VSMCs was enhanced, which played a role in repairing vascular injury. And true to its name, synthetic VSMCs secrete large amounts of collagen, elastin, and matrix metalloproteinase (MMP) causing vascular extracellular matrix (ECM) remodeling. Therefore, synthetic VSMCs almost exist in all types of vascular diseases such as atherosclerosis, aneurysm, neointima. Synthetic VSMCs are prone to further differentiate into alternative phenotypes such as macrophage-like and osteogenic VSMCs.

Vascular calcification (VC) is a common sign in the aged population and chronic kidney disease (CKD) population, which could consequent in increased artery hardness, impaired elasticity, and deficient compliance in advanced stage. VC can be regarded as a process of osteogenesis since the activation of osteogenic genes in the vascular cells play a pivotal role. Recent studies have gradually pointed out the fact that VSMCs switching to the osteogenic phenotype is the principal reason for vascular calcification. Osteogenic VSMCs are also called osteoblast-like VSMCs because of their similarity to osteoblast.

Macrophage-like VSMCs are termed for their similar surface markers and function with macrophages. Macrophage-like VSMCs demonstrate low expression of contractile markers and possess functions similar to macrophages such as innate immune signaling, phagocytosis, and efferocytosis. The phagocytosis of VSMCs in atherosclerosis relies on its macrophage-like phenotype, so high oxidized LDL and cholesterol are the primary metabolic factors driving macrophage-like VSMCs. However, the proportion of macrophage-like VSMCs in the pathogenesis of atherosclerosis is lower than that of macrophage itself, and the level of the inflammatory factors in macrophage-like VSMCs is also inferior to that of monocyte-derived macrophages. The degree of contribution to pathogenesis is unclear.

The VSMCs that express partial mesenchymal markers are referred to mesenchymal-like VSMCs, but there is no uniform official definition of mesenchymal-like VSMCs. The role of mesenchymal-like VSMCs in arterial disease is uncertain. Earlier studies believed that tunica adventitia derived mesenchymal-like VSMCs contribute to atherosclerotic plaque growth and CKD-induced vascular calcification. Whereas, a recent study found that adventitial VSCs did not differentiate into the pathogenic VSMCs in atherosclerosis. Other work has indicated that mesenchymal-like VSMCs can be induced into macrophage-like VSMCs, or into contractile VSMCs, depending on external stimulus conditions.

Single-cell transcriptome revealed that fibroblast-like VSMCs are present in atherosclerotis plaque. Nevertheless, the markers used to mark fibroblast-like VSMCs and mesenchymal-like VSMCs in single cell sequencing overlapped, creating confusion over their definition. In respect of the gene expression profile displayed by single-cell transcriptome, fibroblast-like VSMCs perform three main functions: synthesizing ECM, enforcing cell-matrix adhesion, and promoting cell proliferation. Fibroblast-like VSMCs switching is associated with arterial fibrosis resulting in increased arterial stiffness.

Great progress has been made in the study of the role of VSMCs phenotype transformation in vascular diseases in the past 20 years. VSMCs phenotype switching provides a new perspective for understanding the pathogenesis of vascular diseases. Importantly, the studies of VSMCs phenotypes provide new ideas and targets for pharmacological treatment. As the master switch that controls VSMCs switch from contractile to all pathogenic phenotypes, KLF4 may be the best therapeutic target. Since a large population of miRNAs has similar roles in regulating the VSMCs phenotype, vesicles with several miRNAs can be attempted to reverse the VSMCs phenotype at the lesion site.

Another future challenge is to accurately manipulate VSMCs phenotype switching to not only prevent vascular disease, but also preserve its function in repairing vascular damage. This depends on a rigorous understanding of the biology of each VSMCs phenotypes and their relationship with vascular diseases. The same phenotypic VSMCs plays distinct roles in different stages of disease, and so it may be a better strategy to firstly induce synthetic VSMCs to proliferate to an appropriate number and then convert it into contractile VSMCs, so that the aorta can obtain both strong contractile ability and thick tunica media.

With the steady increase in the number of elderly individuals globally, age-related diseases emerge as a major challenge to health care workers. Apart from functional and structural changes in the kidneys introduced by aging, immune system decline also significantly increases the risk of age-related kidney diseases. Immunosenescence is a loose definition of age-related changes in the innate and adaptive immune responses, which is characterized by shrinkage of naïve immune cell reservoirs, accumulation of late-stage differentiated cells with a senescent phenotype, and immunoglobulin class switching. These changes in the immune system result in two seemingly incompatible aspects: diminished immune response and increased inflammatory response, also known as inflammaging.

Tubular epithelial cells (TECs) senescence and tertiary lymphoid tissue formation occur following acute kidney injury. Senescent kidney cells promote a chronic inflammatory microenvironment, which can subsequently cause local tissue damage, hinder tissue repair, and promote immune system senescence. Intrarenal inflammation underlies the development of renal fibrosis and chronic kidney disease (CKD) later in life. Immunosenescence is exaggerated in patients with CKD and end-stage renal disease (ESRD). Hallmarks of immunosenescence, including decreased naïve T cells, reduced CD28 expression, and increased proinflammatory macrophages, are convincing predictors of mortality in patients with CKD and ESRD. Renal replacement therapy for old patients with ESRD results in a lower acute rejection rate after the kidney transplantation. However, immunosenescence may increase the risk of chronic, but severe, graft failure. In addition, immunosenescence has been reported to speed up during kidney transplantation and immunosuppressive treatment.

Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer, and COVID-19, involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide, the most abundant water-soluble non-protein thiol in the cell, is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage.

GSH activity is facilitated by activation of the Keap1-Nrf2-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory, and immune system responses. GSH exists in the thiol-reduced (98%+ of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response, and disease severity and mortality.

Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and COVID-19 disease. In this review, we emphasize (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging, and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.

The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1+/m-Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal β-galactosidase - an enzyme elevated in tissues of old mice.

A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1+/m mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.

Regenerative medicine has come a long way since the derivation of the first human pluripotent stem cells (hPSC). As a community, we have become better at sourcing stem cells, differentiating them into therapeutic cell types and transplanting them to cure different diseases. To unlock the full potential of stem cell therapies, we need to overcome the immune barrier to transplantation. The human immune system is incredibly discerning in distinguishing between self and non-self, which could be viral or bacterial proteins, malignant cells, and, of course, cells from a genetically non-identical donor. Genetic differences between the donor and the recipient are recognized as alloantigens if they have never been encountered by the host's immune system before (as opposed to autoantigens) and may prompt allograft rejection.

Based on the nature of the genetic polymorphism and how/when they present themselves to the immune system, three types of alloantigens can be distinguished that, together, define the immune barrier. Human leukocyte antigens (HLA) are the immunodominant barrier to cell and tissue transplantation. Minor histocompatibility antigens (miHA) can vary in their expression from cell type to cell type. Neoantigens (NA) can accumulate during prolonged culture and pose a risk of rejection even of cells of autologous origin.

Initial attempts have focused primarily on the major histocompatibility barrier that is formed by the human leukocyte antigens (HLA). More recently, immune checkpoint inhibitors, such as PD-L1, CD47, or HLA-G, are being explored both, in the presence or absence of HLA, to mitigate immune rejection by the various cellular components of the immune system. In this review, we discuss progress in surmounting immune barriers to cell transplantation, with a particular focus on genetic engineering of human pluripotent stem cells and progenitor cells and the therapeutic cell types derived from them.

The negative impact of stress on neurocognitive functioning is extensively documented by empirical research. However, emerging reports suggest that stress may also confer positive neurocognitive effects. This hypothesis has been advanced by the hormesis model of psychosocial stress, in which low-moderate levels of stress are expected to result in neurocognitive benefits, such as improved working memory (WM), a central executive function. We tested the hormesis hypothesis, purporting an inverted U-shaped relation between stress and neurocognitive performance, in a large sample of young adults from the Human Connectome Project (n = 1000, mean age 28.74).

In particular, we investigated whether neural response during a WM challenge is a potential intermediary through which low-moderate levels of stress confer beneficial effects on WM performance. Further, we tested whether the association between low-moderate prolonged stress and WM-related neural function was stronger in contexts with more psychosocial resources. Findings showed that low-moderate levels of perceived stress were associated with elevated WM-related neural activation, resulting in more optimal WM behavioral performance. The strength of this association tapered off at high-stress levels. Finally, we found that the benefit of low-moderate stress was stronger among individuals with access to higher levels of psychosocial resources.

By drawing attention to the dose-dependent, nonlinear relation between stress and WM, this study highlights emerging evidence of a process by which mild stress induces neurocognitive benefits, and the psychosocial context under which benefits are most likely to manifest.

The traditional view of cardiovascular aging is that of age-related adaptations in the heart characterized by increased left ventricular (LV) mass (LVM) and LV hypertrophy (LVH), which are often secondary to increased systolic blood pressure mainly mediated by arterial stiffening. Yet skeletal muscle sarcopenia occurs with aging but may be accelerated in heart failure states. In advanced stages of heart failure, skeletal muscle wasting accompanied by severe exercise intolerance have long been observed in various cohorts.

To date, observations pertaining to the cardiac muscle-skeletal muscle axis among non-heart failure cohorts have provided useful insights. In a population-based cohort of older Asian subjects without clinical cardiovascular disease, skeletal muscle mass was associated with left ventricular mass, independent of age, diabetes mellitus status, and body size. In a selected cohort of frail sarcopenic older European subjects without severe cardiovascular disease (some had mild cardiovascular disease), appendicular lean mass was strongly associated with LVM and cardiac output.

Although advanced age was associated with loss of skeletal muscle mass, the relationship between LVM and skeletal muscle mass appears to be independent of age. Among 228 community adults aged 65-91 years, individuals with low skeletal muscle mass had lower LVM than those without low skeletal mass, without significant interaction between age and LVM. These observations are hypothesis-generating for possible age-related yet age-independent processes that mediate the cardiac and skeletal muscle systems in older persons.

The observations seem to run counter to the dogma of aging-associated LVH, especially in the context of hypertension which dominates aging. Traditionally, cardiac aging has been associated with increased LV wall thickness, with or without myocyte hypertrophy. High LVM, and not low LVM, has been deemed to be clinically unfavorable. The purpose of this perspective is to summarize the background for this syndrome of concern of low LVM, review the body of work generated by various human aging cohorts, and to explore future directions and opportunities for understanding this syndrome.

So, a senescent cell is a cell that has entered a state - a new state. And that state has three compartments. The first compartment is the cell doesn't divide anymore. So it starts out where it can divide if it wants to. But now, it's blocked. And it will never divide again so far as we know. The second is: the cells resist dying. They stick around both in vivo and also in culture when we study these things in human and mouse cultures. And the third thing, which we think is even most important, is they start secreting a lot of molecules that affect their neighbors. Cells with those characteristics increase with age. They're present at sites of age-related pathology in both humans and mice. We think that they're driving aging, and in the mouse, we've proven that. We have not proven it in humans yet.

That senescent cells appear in the brain is driving some neurodegenerative diseases. For example, if we take senescent astrocytes - so they're a support cell within the brain - and incubate them with neurons, healthy human neurons, those two cell types will exist - coexist just fine until we give a little bit of a signal that is common between neurons called glutamate. Senescent astrocytes but not non-senescent astrocytes down-regulate the transporters that get rid of excess glutamate. Excess glutamate kills neurons. We have shown that at senescence, the down-regulation of these proteins that get rid of excess glutamate will cause a neighboring neuron to die in the process of experiencing that glutamate. And that does not happen in a young brain because there are so few senescent astrocytes.

Low-level infiltration of certain immune cells into tissues is called inflammaging. So there are multiple causes of inflammaging, it is a general feature of aging and a general feature of aged tissues. Senescence is one of them. So the type of inflammation that's caused by senescent cells has been called sterile inflammation. There's no evidence for a pathogen. But the immune cells are there. And these immune cells are destructive. So many of them are part of the more primitive part of our immune system called the innate immune system. These guys evolved to get rid of pathogens. And they do it by initially secreting toxic molecules until the more sophisticated part of your immune system called the adaptive immune system can now make the antibodies the other types of proteins that we associate with sophisticated, immune function. So senescent cells attract mostly innate immune cells. But of course, these two immune systems talk to each other. So eventually, you get a full-blown inflammatory response.

There is a mouse where we had eliminated senescent cells. We can manipulate the genome of a mouse pretty well. And we've done that by causing one of these senescent marker genes to drive a foreign gene that is a killer basically but only in the presence of an otherwise benign drug. And so using that mouse, we've shared that mouse with many laboratories, all of them working on a different age-related disease. And they test the hypothesis. Do senescent cells make a difference? And if so, if we eliminate them, is the disease either postponed, which it often is, or ameliorated, meaning it's not so severe. And that often happens - that's why the list of diseases that we know can be driven by senescent cells is so long. And once in a while for a few diseases, it actually can reverse.

Aging is an intricate biological event that occurs in both vertebrates and invertebrates. During the aging process, the brain, a vulnerable organ, undergoes structural and functional alterations, resulting in behavioral changes. The hippocampus has long been known to be critically associated with cognitive impairment, dementia, and Alzheimer's disease during aging; however, the underlying mechanisms remain largely unknown. In this study, we hypothesized that altered metabolic and gene expression profiles promote the aging process in the hippocampus. Behavioral tests showed that exploration, locomotion, learning, and memory activities were reduced in aged mice.

Metabolomics analysis identified 69 differentially abundant metabolites and showed that the abundance of amino acids, lipids, and microbiota-derived metabolites (MDMs) was significantly altered in hippocampal tissue of aged animals. Our metabolomic analysis identified many known MDMs, including short-chain fatty acids, indoles, phenols, nucleotides, and amino acids. Intriguingly, the abundance of several MDMs, such as TMAO and spermidine, was significantly changed in the hippocampus of aging mice. Furthermore, transcriptomic analysis identified 376 differentially expressed genes in the aged hippocampus. The multi-omics analysis showed that pathways related to inflammation, microglial activation, synapse, cell death, cellular/tissue homeostasis, and metabolism were dysregulated in the aging hippocampus.

In conclusion, our data revealed that metabolic perturbations and gene expression alterations in the aged hippocampus were possibly linked to their behavioral changes in aged mice; we also provide evidence that altered MDMs might mediate the interaction between gut and brain during the aging process.

Parkinson's disease (PD) is the second most common neurodegenerative disease. To date, PD is still incurable and its pathogenesis remains elusive. Evidence from experimental studies reveals that mechanisms including protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, and altered gut bacteria composition contribute to PD development. As of now, a number of medication strategies have been widely applied to control the motor and non-motor symptoms of PD and improve the quality of life. However, with long-term application of these drugs and as the disease progresses, adverse effects emerge. Moreover, these medications could neither effectively prevent the disease onset nor stop the disease progression. Recently, lifestyle interventions in the promotion of healthy brain aging and the prevention and treatment of central nervous system (CNS) diseases have risen into the spotlight, which could be promisingly complementary to the conventional PD pharmacotherapy.

Dietary restriction (DR), which involves a moderate reduction in food intake while avoiding malnutrition, has been proven to be effective in holding back aging and relieving age-related chronic diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The beneficial actions of DR involve metabolic, hormonal, and immunomodulatory mechanisms. DR could reduce obesity and visceral fat, thus preventing metabolic risk factors. It increases insulin sensitivity, glucose tolerance, and ghrelin level. It can also induce adipose tissue transcriptional reprogramming, involving ways to regulate mitochondrial bioenergy, anti-inflammatory response, and longevity. Moreover, a potential role of DR in regulating the gut-brain axis has been well described in diseases of CNS and intestinal microbiota transplantation has been shown to be effective in Alzheimer's disease (AD) and multiple sclerosis (MS). Here, we summarize the strategies of DR from clinical and laboratory studies, and review the current findings of DR in preventing and ameliorating PD, with an emphasis on the possible mechanisms.

While skin and many other tissues of the human body retain the ability to repair themselves after injury, the same isn't true of the heart. During human embryonic and fetal development, heart cells undergo cell division to form the heart muscle. But as heart cells mature in adulthood, they enter a terminal state in which they can no longer divide. To understand more about how and why heart cells change with age, researchers looked at nuclear pores. These perforations in the lipid membrane that surround a cell's DNA regulate the passage of molecules to and from the nucleus.

Using super-resolution microscopy, researchers visualized and counted the number of nuclear pores in mouse heart cells, or cardiomyocytes. The number of pores decreased by 63% across development, from an average of 1,856 in fetal cells to 1,040 in infant cells to just 678 in adult cells. These findings were validated via electron microscopy to show that nuclear pore density decreased across heart cell development.

Previously, researchers showed that a gene called Lamin b2, which is highly expressed in newborn mice but declines with age, is important for cardiomyocyte regeneration. In the new study, researchers found that blocking expression of Lamin b2 in mice led to a decrease in nuclear pore numbers. Mice with fewer nuclear pores had diminished transport of signaling proteins to the nucleus and decreased gene expression, suggesting that reduced communication with age may drive a decrease in cardiomyocyte regenerative capacity.

In response to stress such as high blood pressure, a cardiomyocyte's nucleus receives signals that modify gene pathways, leading to structural remodeling of the heart. This remodeling is a major cause of heart failure. The researchers used a mouse model of high blood pressure to understand how nuclear pores contribute to this remodeling process. Mice that were engineered to express fewer nuclear pores showed less modulation of gene pathways involved in harmful cardiac remodeling. These mice also had better heart function and survival than their peers with more nuclear pores.

These findings demonstrate that the number of nuclear pores controls information flux into the nucleus. As heart cells mature and the nuclear pores decrease, less information is getting to the nucleus. A reduced number of communication pathways protects the organ from damaging signals, such as those resulting from high blood pressure, but may also prevent adult heart cells from regenerating.