Researchers have discovered a possible new approach to immunization against Alzheimer's disease (AD). Their method uses a recombinant methionine (Met)-rich protein derived from corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide (MetO)-rich protein. This antigen, when injected to the body, goads the immune system into producing antibodies against the MetO component of beta-amyloid, a protein that is toxic to brain cells and seen as a hallmark of Alzheimer's disease.

"As we age, we have more oxidative stress, and then beta-amyloid and other proteins accumulate and become oxidized and aggregated - these proteins are resistant to degradation or removal. In a previous 2011 published study, I injected mouse models of Alzheimer's disease with a similar methionine sulfoxide-rich protein and showed about 30% reduction of amyloid plaque burden in the hippocampus, the main region where damage from Alzheimer's disease occurs."

The MetO-rich protein used for the vaccination of AD-model mice is able to prompt the immune system to produce antibodies against MetO-containing proteins, including MetO-harboring beta-amyloid. The introduction of the corn-based MetO-rich protein (antigen) fosters the body's immune system to produce and deploy the antibodies against MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce the levels of toxic forms of beta-amyloid and other possible proteins in brain.

The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine of beta-amyloid (Aβ), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of Aβ and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age.

Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced Aβ levels in both blood-plasma and brain; reduced Aβ burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions.

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly extended the lifespan of C. elegans compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms.

The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans.

In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.

Constantly exposed to both internal and environmental stresses such as UV radiation or air pollutants, the skin ages and undergo profound changes in its appearance and functions. Indeed, aged skin undergoes gradual structural and functional degeneration, leading to thinning of epidermal and dermal layers, loss of elasticity, wrinkling, and dryness. These changes are responsible for delayed wounding, more frequent infections, pruritus, enhanced allergen/irritant penetrations with variable degree of dermatitis and eventually carcinogenesis. In rodents and humans, these phenomena have been partially attributed to loss or lineage skewing of keratinocytes stem cells and immune cells, and/or the regulation of their niches, altering normal homeostasis and tissue repair.

Naked mole-rats (NMRs) are small poikilothermic and hairless rodents native to East Africa, where they live underground in eusocial colonies. These mouse-sized rodents live almost five times longer than expected on the basis of body size, with a maximum lifespan exceeding 37 years in captivity and up to 17 years in their natural habitat. Despite being the longest-lived rodent, NMR do not show any increase in age-specific hazard of mortality in defiance of Gompertz's law and all of the classical signs of aging such as decreased fertility, muscle atrophy, bone loss, changes in body composition or metabolism seem to be mostly absent in these animals.

We used single-cell RNA-sequencing (scRNA-seq), to obtain the unbiased molecular RNA profile of the NMR epidermal cell populations. By profiling 10,000+ cells from skin epidermis in young and older NMR, we found that epidermal compartments and cell populations, especially the stem cells pool, remained unaffected despite aging. Igfbp3, expressed by keratinocyte stem cells and known to play a major role during epidermal homeostasis, was found upregulated in older animals, contrary to what is observed in other species. In addition, functional skin healing experiments revealed that NMR skin healing closure was similar in young and older animals.

Cerebrospinal fluid (CSF) from young mice can improve memory function in older mice. A direct brain infusion of young CSF probably improves the conductivity of the neurons in ageing mice, which improves the process of making and recalling memories. The researchers also isolated a protein from the CSF cocktail that another analysis had suggested was a compelling candidate for improving memory: fibroblast growth factor 17 (Fgf17). Infusion of Fgf17 had a similar memory-restoring effect to infusing CSF. Furthermore, giving the mice an antibody that blocked Fgf17's function impaired the rodents' memory ability.

It took more than a year to perfect the process of collecting CSF and infusing it into another brain. Collection is extremely challenging, and has to be done with precision. Any blood contamination will ruin the fluid. Pressure in the brain is a delicate balance, so infusion must be slow and in a specific location within the brain: the cerebral ventricle. The delicate procedure might pose challenges for use in people.

Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures.

We identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

Over the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries.

Performing clinical trials to study the anti-aging potential of conventional drugs is undoubtedly a very difficult task. This is because older patients often suffer from multiple diseases and receive multiple medications simultaneously. The presence of drug-drug interactions and identified comorbidities make the evaluation of such drugs difficult, especially to assess the full range of effects produced by these drugs, whether beneficial or harmful. The lack of reliable and detectable biomarkers to assess the effectiveness of anti-aging interventions is another serious challenge.

The criteria for a potential anti-aging drug are: (1) a drug that extends the lifespan of a model organism, preferably a mammal; (2) a drug that delays or prevents some aging-related diseases in mammals; and (3) a drug that inhibits the senescence transition of cells from quiescence to senescence. The criteria may overlap. If an intervention is intended to extend lifespan, it must retard diseases associated with aging.

Many plants and fungi contain natural anti-aging products that can extend the lifespan of model organisms. These active molecules regulate the same cellular and physiological pathways that are affected by calorie restriction (CR) and exercise. Compounds that increase lifespan and healthspan mimic the effects of CR, typically by reducing insulin/IGF-1 signaling and activating autophagy and other cellular processes that increase resistance to stress.

Various strategies exist for using the anti-aging agents described here, including dietary supplements, increasing the intake of foods containing large amounts of these molecules, and/or consuming probiotics and prebiotics that raise blood levels of these molecules. Several nutrients and natural compounds have been observed to be related to increased lifespan in humans, suggesting that such strategies are feasible for slowing aging and increasing health span. Plant and fungal molecules with anti-aging properties in model organisms may also lead to the discovery and identification of new bioactive compounds for the development of improved CR mimetics to slow human aging. Except for mentioned above natural products, many other compounds have been reported to show anti-aging activity, such as acetic acid, allicin, apigenin, aspalathin, berberine, capsaicin, catalpol, celastrol, garcinol, huperzine, hydroxycitrate, inositol, naringin, piceatannol, and piperlongumine.

Biogerontology is entering a period of exciting and rapid development. It has great potential for future pharmacological interventions to slow aging. As a new era of anti-aging drug discovery dawns, the research community will need to pay special attention to the timely development of drugs that can slow the aging process, either alone or as multiple agents. Natural products provide the driving force to move forward in our quest to understand and improve the health span, just as they have always done! In regulating aging, it is hoped that these drugs will also reduce the burden of many age-related diseases.

Desired longevity represents how strongly people esteem possible extensions of their own lifetime. The association between desired longevity and mortality risk has been reported in only one prospective study, which examined a small sample of older participants. We aimed to examine the hypothesis that desired longevity at middle-age predicted long-term survival.

In the prospective cohort study, residents aged 40-64 years were asked how long they would like to live and asked to choose one from three options: longer than, as long as, or shorter than the life expectancy. 39,902 residents were recruited to the study. Risk of all-cause mortality was significantly higher in the "shorter than" group (hazard ratio 1.12). The association was independent of sex, age, marital status, education, medical history, and health status. Regarding cause of death, mortality risk of cancer (hazard ratio 1.14) and suicide (hazard ratio 2.15) were also higher in the "shorter than" group. The unhealthy lifestyle mediated this association with all-cause mortality by 30.4%.

In conclusion, shorter desired longevity was significantly associated with an increased risk of all-cause mortality, and mortality from cancer and suicide. Lifestyle behaviors particularly mediated this association.

Vascular calcification is an irreversible pathological process associated with a loss of vascular wall function. This process occurs as a result of aging and age-related diseases, such as cardiovascular and chronic kidney diseases, and produces comorbidities. During these age-related diseases, the endothelium accumulates senescent cells, which stimulate calcification in vascular smooth muscle cells. Currently, vascular calcification is a silent pathology, and there are no early diagnostic tools. Therefore, by the time vascular calcification is diagnosed, it is usually untreatable.

Some mediators, such as oxidative stress, inflammation, and extracellular vesicles, are inducers and promoters of vascular calcification. They play a crucial role during vascular generation and the progression of vascular calcification. Extracellular vesicles, mainly derived from injured endothelial cells that have acquired a senescent phenotype, contribute to calcification in a manner mostly dependent on two factors: (1) the number of extracellular vesicles released, and (2) their cargo. In this review, we present state-of-the-art knowledge on the composition and functions of extracellular vesicles involved in the generation and progression of vascular calcification.

Maintenance of physical performance is essential for achievement of healthy aging. A few studies have explored the association between inflammatory markers and physical performance in older adults with inconclusive results. Our aim was to analyze the association of tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), and C-reactive protein (CRP) with physical performance in a sample of older adults in rural settings of Mexico. Our study comprised 307 community-dwelling older men and women who participated in the third wave of the Rural Frailty Study.

In comparison with the normal physical performance group, low physical performance individuals mainly were female, older, more illiterate, more hypertensive, fewer smokers, and had higher CRP levels. The logistic model results showed a significant association between the 3rd tertile of CRP and low physical performance (odds ratio = 2.23). IL-10 and TNF-α levels did not show a significant association. The results of this study were thus mixed, with a significant association of physical performance with higher CRP levels but nonsignificant with IL-10 and TNF-α. Further studies with improved designs are needed by incorporating a broader set of inflammatory markers.

A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia, multi-nucleate cells resulting from fusion.

Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau, and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia.

In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a "decentralized" information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity.

Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span.

A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.

Emerging evidence has shown that senescent astrocytes are involved in initiating and promoting the progression of Alzheimer's disease (AD). Senescent astrocytes exhibit expression of senescence-associated secretory phenotype (SASP). It has been reported that the number of senescent astrocytes in the frontal cortex of AD patients is significantly higher than that of non-AD adults with similar ages. Accumulation of senescent astrocytes produces massive secretion of SASP factors, reduces amyloid-β clearance, promotes aggregation of insoluble tau. Elimination of these senescent glial cells, including astrocytes, prevents the hyperphosphorylation of tau protein, neurofibrillary tangles, and cognitive hypofunction.

Yes-associated protein (YAP), as a co-activator and multi-functional protein, is a critical effector of the Hippo pathway, and has been shown to inhibit the senescence of various types of cells. Recently, we have found that YAP is down-regulated and inactivated in senescent astrocytes, not only in cultured senescent astrocytes, but also in hippocampal astrocytes of the aging mice and AD model mice, in a Hippo pathway-dependent manner, indicating a role of YAP in astrocytic senescence.

Cyclin-dependent kinase 6 (CDK6), as a downstream molecule of YAP, is decreased in YAP knockout astrocytes in vivo and in vitro, and over-expression of CDK6 partially rejuvenates YAP knockout astrocytes, indicating that YAP inhibits astrocytic senescence through the CDK6 signaling. Moreover, activation of YAP improves the cognitive decline of AD model mice. This evidence exhibits the positive potential of the YAP-CDK6 pathway in restraining astrocytic senescence in AD.

You could argue that there are some really simple model systems where we can reverse aging. You could also argue that we can reverse aging in human cells with telomerase and cellular reprogramming with Yamanaka factors, but whether that applies to whole organs is a completely different question. The jury is still out on whether we can actually reverse aging in mammals.

I think this might be a terminology issue. If you take an obese individual, and this individual goes on a diet, they will be healthier. Their risks from various age-related diseases are going to decrease because of the diet, but that doesn't mean that this person has been rejuvenated, it just means that a lifestyle intervention improved their health.

A lot of times, you can have interventions that improve health and maybe ameliorate elements of epigenetic clocks without necessarily doing anything about the process of aging. I think we've had this problem in the field for quite a long time - that you can have interventions that increase longevity without necessarily retarding aging, just because they're healthy. Do obese individuals age faster? I wouldn't readily assume so, although some of my colleagues may disagree with me.

You can have interventions, pharmacological interventions, for instance, that extend lifespan, but don't slow down aging in humans and even in model systems. Mice mostly die of cancer, and if you have a drug that prevents cancer, the mice are going to live longer. It doesn't mean aging has been retarded, even though longevity has increased. The problem we have in the field is what do those various interventions mean? Do they really slow aging, do they reverse aging, or are they just healthy? That's why we sometimes need to be more careful about what we are claiming to have achieved.

How would you show something like aging reversal? To me, there's still a question mark on it. I think you must have some pretty strong evidence for it - functional evidence, molecular evidence. It has to be something quite substantial to prove that you've reversed aging in a mammalian organism, that you've rejuvenated a tissue. I think that would require some pretty substantial evidence which I haven't seen yet. Going back to the question, in complex models, such as mammals - no, I don't think we have really reversed aging.

Axonal regeneration and neurological functional recovery are extremely limited in the elderly. Consequently, injuries to the nervous system are typically followed by severe and long-term disability. We hypothesized that injuries to the aged nervous system would be followed by unique molecular and cellular modifications that would contribute to aging-dependent regenerative decline. To this end, molecular and cellular signatures associated with aging and injury to the nervous system were systematically investigated by performing RNA sequencing from dorsal root ganglia (DRG) in a well-established model of sciatic nerve injury in young versus aged mice.

Initial analysis of RNA sequencing data identified that aging was mainly associated with a marked increase in T cell activation and signaling in DRG after injury. Subsequent experiments demonstrated that aging was associated with increased inflammatory cytokines in DRG both preceding and following sciatic nerve injury. Specifically, we found that lymphotoxin β was required for the phosphorylation of NF-κB that drives the expression of the chemokine CXCL13 in DRG sensory neurons. CXCL13 attracted CD8+ T cells that expressed the CXCL13 receptor CXCR5 in proximity to neurons that act as antigen-presenting cells by overexpressing major histocompatibility complex class I (MHC I) after injury. The engagement of CXCR5+CD8+ T cells with MHC I-expressing sensory neurons activated caspase 3, which produces regenerative failure.

Neutralization of CXCL13 with monoclonal antibodies reduced the recruitment of CXCR5+CD8+ T cells to the DRG and restored the regenerative ability of sciatic sensory axons in aged mice to levels comparable to those found in young animals. CXCL13 antagonism also significantly promoted skin reinnervation and neurological recovery of sensory function.

The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie - and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine.

Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality - the specific composition of dietary protein - may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.

The gut microbiota is associated with the health and longevity of the host. Through the aging process, age-related changes in the composition of gut microbiota have been observed, which are related to increased intestinal disorders, inflammation, cognitive decline, and increased frailty. Furthermore, remodeling of the gut microbiome has resulted in a prolonged lifespan in Drosophila melanogaster, killifish, and progeroid mice. Previous studies have clearly shown that delivery of a healthy microbiome through co-housing or fecal microbiota transplantation (FMT) enhances intestinal immunity and facilitates healthy aging.

The changes in host microbiomes still remain poorly understood. Here, we characterized both the changes in gut microbial communities and their functional potential derived from colon samples in mouse models during aging. We achieved this through four procedures including co-housing, serum injection, parabiosis, and oral administration of Akkermansia muciniphila as probiotics using bacterial 16 S rRNA sequencing and shotgun metagenomic sequencing.

These rejuvenation procedures restore age-dependent alterations in intestinal function and inflammation. Furthermore, oral administration of Akkermansia led to an improvement in the frailty index. The generated data expand the resources of the gut microbiome related to aging and rejuvenation and provide a useful dataset for research on developing therapeutic strategies to achieve healthy active aging.