Fight Aging! Newsletter, December 31st 2018

Transforming growth factor type beta 1 (TGF-β1) is a growth factor and cytokine belonging to a superfamily of ligands, including bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and myostatin, which are pleiotropic factors with important roles in inflammation, cell growth, and tissue repair. TGF-β1 mediates many of its intracellular actions by changes in the gene expression to regulate the synthesis of extracellular matrix (ECM) proteins, cell motility and several cellular processes, including differentiation, renewal, and quiescence. In skeletal muscle, TGF-β1 can be activated and/or up-regulated by different stimuli, such as acute skeletal muscle injury, or in other cases by chronic stimulus generated in different types of skeletal muscle diseases in which fibrosis and/or atrophy is produced.

Skeletal muscle is a tissue that has the capacity to regenerate after damage, with the replacement of injured tissue by healthy and functional tissue. The regenerative capacity of adult skeletal muscle is attributed to a population of resident stem cells called satellite cells (SC). In normal conditions, SCs are in a quiescent status. However, after damage or in response to degenerative stimuli, the activation of SCs is induced. The formation of mature myofibers and the regeneration process can be impaired or arrested by several mechanisms, such as the inhibition of cell cycle entry, increment of cell death and/or premature terminal commitment. TGF-β1 is a typical inhibitor of the myogenic differentiation process because it can cause SC apoptosis and potently inhibit its proliferation and fusion, negatively affecting muscle regeneration. In this context, in aged regenerating skeletal muscle, TGF-β1 signalling is abnormally elevated and considered to inhibit SC activation and terminal myogenic differentiation.

Fibrosis is formed by the accumulation of ECM proteins, such as fibronectin, collagen, elastin, and laminin, among others, which are produced within the tissue via activation of different fibrogenic factors or cytokines, such as TGF-β1. In several muscular dystrophies, the synthesis and accumulation of ECM components produce the progressive replacement of functional muscle tissue by connective tissue, with the consequent loss of muscle function. Several reports have shown that TGF-β1 has a key role in the inflammatory process in skeletal muscle and induces muscle fibrosis by increasing collagen, fibronectin and other profibrotic factors, such as connective tissue growth factor (CTGF).

The increased knowledge about the participation of TGF-β1 in several muscular pathologies has attracted great interest in the evaluation of therapeutic alternatives to neutralise or diminish the deleterious effects of TGF-β1. Among the possible strategies to inhibit TGF-β signalling are blocking antibodies for TGF-β1, and the different components of RAS and several inhibitors of the TGF-β1 receptors or signalling pathway have been proposed. The main problem with the use of therapies aiming at inhibiting TGF-β1 signalling is the lack of specificity of the compounds and therefore the development of side effects. The challenge is to develop therapy that can specifically promote muscle regeneration while decreasing fibrosis and atrophy without altering the normal function of TGF-β in other tissues, such as regulation of proliferation, haematopoiesis, migration, or inflammation.

Women live longer than men around the world, regardless of culture or socioeconomic status. Female longevity is also observed in the animal kingdom due to causes that may be extrinsic, intrinsic, or both. Extrinsic causes of sex difference in invertebrates can signal antagonistic survival strategies: female pheromones reduce male lifespan in Drosophila, and male secretions shorten hermaphrodite lifespan in C. elegans. Intrinsic effects - operating within the organism - underlie longer life in organisms following removal of reproductive cells or organs in C. elegans hermaphrodites, male and female dogs, and possibly men as suggested by a study of eunuchs. Nonetheless, causes of intrinsic sex difference in lifespan remain largely unknown. The pervasive nature of female longevity in humans, even in early death during severe epidemics and famine, suggests a role for innate biology in the survival gap between the sexes. Here, we sought to identify intrinsic causes of female longevity in mammalian lifespan.

Sex chromosomes or gonads cause intrinsic sex differences in mammals, but whether they directly contribute to increased female lifespan is unknown in mammalian aging. To dissect these etiologies, we used four core genotypes (FCG) mice. In mice and humans, the Sry gene normally resides on the Y chromosome and codes for a protein (testicular determining Y factor) that induces development of testes and perinatal masculinization. In FCG mice, Sry resides instead on an autosome, enabling inheritance of Sry - and thus male, testicular phenotype - with or without the Y chromosome. The genetic manipulation of SRY generates XX and XY mice, each with either ovaries (O) or testes (T): XX(O), XX(T), XY(O), XY(T). Gonadal hormone levels in FCG mice with the same gonads are comparable, regardless of their sex chromosomes. In FCG model mice, a sex difference with a main effect that statistically differs by genotype (XX vs. XY) is sex chromosome-mediated; one that differs by phenotype (ovaries vs. testes) is gonadal sex-mediate. Examples of age-relevant FCG mouse studies show that XX improves blood pressure regulation and attenuates experimental brain injuries.

To explore sex-based differences in lifespan, we generated and aged over 200 mice from the FCG model on a congenic C57BL/6J background and investigated aging-dependent mortality from midlife to old age (12-30 months). We first examined whether mortality in "typical" females (XX,O) and males (XY,T) recapitulates the pattern of female longevity. Indeed, aging females (XX,O) lived longer than aging males (XY,T). We next measured main effects of sex chromosomes and gonads on survival in aging. XX mice with ovaries or testes lived longer than XY mice of either gonadal phenotype, indicating a main effect of sex chromosomes on lifespan. Mice with ovaries (XX and XY) tended to live longer than those with testes (XX and XY), suggesting a gonadal influence on lifespan. Collectively, these data indicate that the XX genotype increases survival in aging - and suggest a protective effect of ovaries.

Mitochondrial disorders are the most common class of inherited errors of metabolism. However, effective treatments are lacking, and their clinical management remains largely supportive. In patients with electron transport chain complex III (cIII) deficiency, mutations in several genes encoding either cIII subunits or assembly factors have been identified. These compromise cIII enzymatic activity and result in a wide variety of clinical manifestations.

BCS1L mutations are the most common cause of cIII deficiency, with various neonatal and adult phenotypes described worldwide, the most severe and prevalent of them being GRACILE syndrome. BCS1L is a mitochondrial inner membrane translocase required for correct function of cIII. Homozygous Bcs1lc.A232G (Bcs1lp.S78G) knock-in mice bearing the GRACILE syndrome-analogous mutation recapitulate many of the clinical manifestations, and a short survival of 35 days. In the slightly different C57BL/6JCrl substrain, the mice develop the same early manifestations but do not succumb to the early metabolic crisis. This extends their survival to over 150 days and brings additional later-onset phenotypes.

Under physiological conditions, quinols that transport electrons in the mitochondrial inner membrane are efficiently oxidized by cIII, with electron transfer via cytochrome c and cytochrome c oxidase (complex IV, cIV) to oxygen. However, plants and some lower organisms, but not mammals, express alternative oxidases (AOXs) that transfer electrons directly from quinols to oxygen. Their main role is to maintain electron flow when the cIII-cIV segment of the electron transport chain is impaired, limiting production of ROS and supporting redox and metabolic homeostasis.

Ciona intestinalis AOX has been cloned and expressed in human cultured cells, fruit flies, and mice. In these models, AOX is inert under non-stressed conditions, most likely because it accepts electrons only when the quinone pool is highly reduced, such as under inhibition or overload of cIII or cIV. Accordingly, upon inhibition of cIII or cIV by mutations or chemical inhibitors, ectopic AOX can maintain respiration and prevent cell death.

We set out to test whether AOX expression could prevent the detrimental effects of cIII deficiency in a mammalian model, by restoring electron flow upstream of cIII. To this end, we crossed mice carrying a broadly expressed AOX transgene with the Bcs1lc.A232G mice and assessed disease progression, organ manifestations, and metabolism in the homozygotes with and without AOX expression.

The mice expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.

Researchers focused on a type of skin cell called dermal fibroblasts, which generate connective tissue and help the skin to heal after injury. They chose this type of cell for two reasons: first, the cells are easy to obtain with a simple, non-invasive skin biopsy; second, earlier studies indicated that fibroblasts are likely to contain signatures of aging. This is because, unlike most types of cells that completely turn over every few weeks or months, a subset of these cells stays with us our entire lives.

The investigators analyzed fibroblasts taken from 133 healthy individuals ranging in age from 1 to 94. To get a representative sample, the team studied an average of 13 people for each decade of age. The lab cultured the cells to multiply, then used a method called RNA sequencing (RNA-Seq) to look for biomarkers in the cells that change as people get older. RNA-Seq uses deep-sequencing technologies to determine which genes are turned on in certain cells. Using custom machine-learning algorithms to sort the RNA-Seq data, the team found certain biomarkers indicating aging, and were able to predict a person's age with less than eight years error on average.

Researchers have discovered age- and health-related differences in fragments of DNA found floating in the bloodstream (not inside cells) called cell-free DNA (cfDNA). These differences could someday be used to determine biological age - whether a person's body functions as older or younger than their chronological age. In a proof-of-concept study, researchers extracted cfDNA from blood samples from people in their 20s, people in their 70s, and healthy and unhealthy centenarians.

They found nucleosomes - the basic unit of DNA packaging in which a segment of DNA is wrapped around a protein core - were well-spaced in the DNA of the volunteers in their 20s but were less regular in the older groups, especially the unhealthy centenarians. Additionally, the signal from nucleosome spacing for the healthy centenarians was more similar to the signal from the people in their 20s than people in their 70s. Nucleosome packing is one aspect of the epigenome. Scientists first found cfDNA in the blood of cancer patients, and the fragments can be useful for diagnosing cancer. Earlier research has found that cfDNA is produced by dying cells, and as the cells die, the DNA is cut in between nucleosomes. "cfDNA is somewhat like a message in a bottle that captures what the cell looked like, epigenetically speaking, before it died."

Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell (PBMC) telomere length, circulating Aβ peptides, anti-Aβ antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians (n = 20) and functionally impaired, institutionalized nonagenarians (n = 38) recruited between 2014 and 2015.

We recruited 58 nonagenarians (41 women, mean age: 92.37 years, in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths, this being inversely correlated with functional impairment, and lower circulating Aβ40, Aβ42, and Aβ17 levels, after adjusting by age. Although healthy nonagenarians had higher anti-Aβ40 antibody levels, the number of participants that pass the threshold to be considered as positive did not show such a strong association. There was no association with ApoE status.

Cellular senescence, a central component of aging, is a cell-intrinsic stress response programmed to impose stable cell-cycle arrest in damaged cells, thus preventing them from propagating further damage in tissues. Normally, a sequence of events leads to the clearance of senescent cells and allows regeneration of the tissues that harbor them. In advanced age, however, the efficiency of this process may be compromised, as suggested by the tendency of senescent cells in the tissues of old individuals to accumulate. This accumulation is reportedly conserved across different species, including rodents, primates, and humans. Under such conditions, the beneficial cell-autonomous role of senescence might be outstripped by a negative impact of senescent cells on other cells, an effect mediated via the senescence-associated secretory phenotype (SASP), which has marked pro-inflammatory characteristics.

Senescent cells are subject to immune surveillance by multiple components of the immune system. Senescent cells attract and activate immune cells and serve as highly immunogenic targets for immune clearance. The immune response that is against senescent cells varies with different pathological conditions. For example, in fibrotic livers senescent cells derived from activated hepatic stellate cells are cleared by natural killer (NK) cells, whereas senescent pre-malignant hepatocytes are eliminated via the adaptive immune system. In other pathological conditions, for example in the case of dysplastic nevi, immune clearance does not occur and senescent cells persist for years. In the context of aging, it is not known to what extent the immune system participates in regulating the number of senescent cells, and whether age-related impairment of immune function contributes to the accumulation of senescent cells in old individuals.

Perforin, a pore-forming protein found in intracellular granules of effector immune cells, is an important mediator of immune cytotoxicity. Upon degranulation, perforin-formed pores enable granzyme penetration and caspase activation to induce apoptosis of the target cell. Perforin-mediated granule exocytosis (but not death-receptor-mediated apoptosis) is essential for the immune surveillance of senescent cells, and disruption of this pathway leads to the accumulation of senescent cells in damaged livers. To investigate the consequences of impaired immune surveillance of senescent cells in aging, we followed the aging process in mice in which granule-exocytosis-mediated apoptosis was disabled as a result of perforin gene knockout (Prf1-/-).

Our data indicates that compared to wild-type (WT) mice, Prf1-/- mice accumulates more senescent cells in their tissues with age. The accumulation of senescent cells in these Prf1-/- mice is accompanied by a progressive state of chronic inflammation, followed by increased tissue fibrosis and other types of tissue damage, as well as compromised organ functionality. The poor health of old Prf1-/- mice is associated with fitness reduction, weight loss, kyphosis, older appearance, and shorter lifespan than that of WT controls. Elimination of senescent cells from old Prf1-/- mice can be achieved by pharmacological inhibitors of the BCL-2 family of proteins, such as ABT-737. This pharmacological approach attenuates age-related phenotypes and gene expression profile in Prf1-/- mice.

To our knowledge, the first study reporting cell rejuvenation was published in 2011. It was known that cells from old individuals display a typical transcriptional signature, different from that of young counterparts. It was also known that fibroblasts from old donors have shortened telomeres as well as dysfunctional mitochondria and higher levels of oxidative stress. The researchers first explored the effect of cell reprogramming on the above features. In order to efficiently reprogram fibroblasts from healthy centenarians and very old donors, the authors added the pluripotency genes NANOG and LIN28 to the Yamanaka OSKM reprogramming cocktail. This six-factor combination efficiently reprogrammed fibroblasts from very old donors into typical induced pluripotent stem cells (iPSCs).

These blastocyst-like cells showed a higher population-doubling (PD) potential than the cells of origin as well as elongated telomeres and a youthful mitochondrial metabolism (estimated by measuring mitochondrial transmembrane potential and clustering transcriptome subsets involved in mitochondrial metabolism). Using an appropriate differentiation cocktail, the iPSCs were differentiated back to fibroblasts, whose transcriptional profile, mitochondrial metabolism, oxidative stress levels, telomere length, and PD potential were indistinguishable from those of fibroblasts from young counterparts. Taken together, the data revealed that the cells had been rejuvenated.

Until late 2016, it was believed that although cells taken from old individuals could be fully rejuvenated, rejuvenation in vivo was not possible as a continuous expression of the Yamanaka OSKM genes in animals had been shown to cause multiple teratomas. However, then it was reported for the first time that cells and organs can be rejuvenated in vivo. The authors used transgenic progeric mice. After 6 weeks of partial reprogramming cycles, the experimenters could observe some improvements in the external appearance of experimental mice, including a reduction in spine curvature as compared with untreated counterparts (controls).

A subgroup of the experimental and control mice was sacrificed and some of their tissues and organs analyzed (skin, kidneys, stomach, and spleen). Controls showed a variety of alterations at an anatomical and histological level in the above organs whereas some of these aging signs disappeared or were attenuated in the experimental mice. Some aging signs remained unchanged by the treatment. Furthermore, although the experimental animals kept aging, they showed a 50% increase in mean survival time as compared with wild-type progeric controls. If the treatment was interrupted, the aging signs came back.

Aging is characterized by the accumulation of various forms of damage as well as by other age-related deleterious changes. These changes generally have negative, deleterious consequences for organisms as they age. Different living systems differ in their metabolic strategies, resulting in different types and levels of damage production, therefore have evolved both unique and common mechanisms to counteract some of these deleterious changes. These mechanisms also limit the transfer of damage to progeny. The damage-producing and protective mechanisms are mostly genetically controlled, differ among taxonomic groups and are important in defining the lifespan of organisms. Nevertheless, the general principles of cell and organismal organization make damage accumulation inevitable for most multicellular organisms.

In this review, we discuss age-related changes in one of the most important and abundant components of any cell, and therefore of the whole organism - the proteome. Functionality of the whole system of proteins in any organism requires maintenance of a precise balance of synthesis, degradation and function of each and every protein, while aging often shifts this balance, resulting in pathology. Being the end-point of the implementation of genetic information, the proteome accumulates damage generated during this process. The effectiveness of proteostasis control systems, which maintain and recycle the proteome, is diminished with age, leading to the accumulation of damaged proteins and molecules, which in turn inhibit cell functionality and thus cause age-related dysfunction.

Every step in protein lifecycle, most notably protein synthesis and degradation, is relevant to the aging process and, indeed, has been shown to change with age and likely define lifespan. While changes in protein degradation systems during aging are relatively well studied, alterations in protein synthesis still remain to be elucidated. Does the overall level of protein synthesis change with age? Which components of the translation apparatus are affected by aging? Do errors in protein synthesis increase in older organisms? Is there age-dependent regulation of protein synthesis at the level of translation? Answering these questions is necessary for understanding the mechanisms of aging and lifespan control.

To a large extent our well-being depends on what bacterial guests in our digestive tract consume. That's because gut flora help the human body to utilize food and produce essential micronutrients, including vitamins. Beneficial gut microbes can produce metabolites from dietary fiber, including a fatty acid called propionate. This substance protects against the harmful consequences of high blood pressure. Researchers have now shown why this is the case. The researchers fed propionate to mice with elevated blood pressure. Afterwards, the animals had less pronounced damage to the heart or abnormal enlargement of the organ, making them less susceptible to cardiac arrhythmia. Vascular damage, such as atherosclerosis, also decreased in mice.

"Our study made it clear that the substance takes a detour via the immune system and thus affects the heart and blood vessels." T helper cells, which enhance inflammatory processes and contribute to high blood pressure, were calmed. This has a direct effect on the functional ability of the heart. The research team triggered heart arrhythmia in 70 percent of the untreated mice through targeted electrical stimuli. However, only one-fifth of the animals treated with the fatty acid were susceptible to an irregular heartbeat. Further investigations with ultrasound, tissue sections, and single-cell analyses showed that propionate also reduced blood pressure-related damage to the animals' cardiovascular system, significantly increasing their survival rate. But when researchers deactivated a certain T cell subtype in the mice's bodies, known as regulatory T cells, the positive effects of propionate disappeared. The immune cells are therefore indispensable for the substance's beneficial effect.

Propionate still has to prove itself in everyday clinical practice. The research team now hopes to validate their findings by examining the substance's effects on human subjects. It is already known that propionate is safe for human consumption and can also be produced economically: The substance has been used for centuries as a preservative, for example. It is already approved as a food additive. "With these favorable conditions, hopefully propionate will soon make the leap from the lab to patients who need it."

Just a generation ago, common wisdom held that once a person reaches adulthood, the brain stops producing new nerve cells. Scientists countered that depressing prospect 20 years ago with signs that a grown-up brain can in fact replenish itself. The implications were huge: Maybe that process would offer a way to fight disorders such as depression and Alzheimer's disease. This year, though, several pieces of contradictory evidence surfaced and a heated debate once again flared up. Today, we still don't know whether the fully grown brain churns out new nerve cells.

In March of this year, contradicting several landmark findings that had convinced the scientific community that adults can make new nerve cells, researchers described an utter lack of dividing nerve cells, or neurons, in adult postmortem brain tissue. A return volley came a month later, when a different research group described loads of newborn neurons in postmortem brains, in an April paper. Scientific whiplash ensued when a third group found no new neurons in postmortem brains, describing the results in July. Still more neuroscientists jumped into the fray with commentaries and perspective articles.

This ping-ponging over the rejuvenating powers of the brain is the most recent iteration of a question on neurogenesis that still hasn't been answered. Despite the more recent negative results, many scientists still hold on to the notion that new growth happens. "The negative findings were very controversial. It's always very difficult to put aside a phenomenon just by not finding it. Let's face it: it's not easy to label and detect adult neurogenesis in human postmortem tissue. This year's studies provide a push to the field to develop more advanced tools and models."

Finding ways to prevent age-related diseases is important because the aging population is snowballing in the world as a result of better nutrition, effective antibiotics against infectious diseases, and improved healthcare. Development of interventions that slow down the rate of aging and reduce or postpone the incidence of debilitating age-related diseases would be of immense value to improve the quality of life as well as to reduce medical costs. Studies in animal models have demonstrated that a variety of genetic, dietary, and pharmacological interventions enhance lifespan. Some of the anti-aging strategies that extend lifespan may also be useful for delaying the onset of age-related diseases.

Autophagy has a significant role in the modulation of the aging process. The function of autophagy in aging is apparent from numerous studies using yeasts, worms, flies, and mice that elevated expression of autophagy-related genes is a prerequisite for lifespan extension. Some studies have also shown that tissue-specific expression of single autophagy gene is adequate for extending lifespan whereas other studies have pointed out that distinct types of autophagy are critical for longevity as they specifically target dysfunctional cellular components and prevent their aberrant accumulation. Interestingly, slow-down of aging and longevity increase achieved through food deprivation and calorie restriction (CR) are facilitated through upregulation of autophagy. Thus, autophagy enhancing interventions that commence in middle age would likely facilitate successful aging and increased longevity.

Amongst the perpetrators of organismal aging, the function of senescent cells (SCs) has caught significant interest. Senescent cells disrupt the milieu by producing a plethora of bioactive factors that cause inflammation and impede regeneration. Senescent cells actively propel spontaneously ensuing age-related tissue deterioration and thereby promote several diseases associated with aging. In several tissues and organs, senescence is a common feature during the aging process with an age-related increase in the number of senescent cells. From the above, it appears that, the elimination of senescent cells using drugs referred to as senolytics would slow down aging and maintain better function during old age. In mice, senotherapy proved to be effective in models of accelerated aging and also during normal chronological aging. Senotherapy prolonged lifespan, rejuvenated the function of bone marrow, muscle and skin progenitor cells, improved vasomotor function and slowed down atherosclerosis progression.

A new procedure for limiting or reversing aspects of aging in various organs throughout the body is the transfusion of blood from the young to the aged, as molecules circulating in the young blood can rejuvenate the aging cells and tissues. Studies suggested that several soluble factors underlie the rejuvenating effects of the young blood. The growth differentiation factor 11 (GDF11) is one of the well-characterized factors in the young blood. Clinical trials testing the effect of young plasma in patients with Alzheimer's disease are already underway, but careful, placebo-controlled larger clinical trials will be required.

Recently, many studies have shown that intermittent fasting (IF) can have similar effects as CR. Benefits related to cardiovascular health include protection of heart against ischemic injury, reduced body mass index and blood lipids, improved glucose tolerance, and lower incidence of coronary artery disease. The positive effects of IF on brain health in pre-clinical studies comprised improved cognitive function with reduced oxidative stress during middle age when IF was commenced in young adult age and delayed occurrence of age-related brain impairments. In human studies, protocols and interpretations of IF-mediated weight loss trend varied considerably. Most human IF studies did not result in significant weight loss or considerable improvements in metabolic biomarkers. Quite a few questions remain to be dealt with regarding the benefits of IF on human health.

Studies in animal models have shown that hippocampal neurogenesis decreases during aging, and the overall decrease is exacerbated in Alzheimer's disease. The precise mechanistic causes underlying age-related decline in neurogenesis are unclear. Overall, it appears that age-related reductions in stem cell mitogenic factors, microvasculature and cerebral blood flow, and low-grade inflammation influence reduced neurogenesis in aging because increased neurogenesis could be obtained through interventional strategies that upregulate the concentration of neural stem cell (NSC) mitogenic factors or improve the microvasculature density and diminish inflammation. Pharmacological mimetics of exercise capable of enhancing both hippocampal neurogenesis and BDNF appear to be useful for improving cognitive function, and thus combined neurogenesis and BDNF boost during adulthood and middle age may postpone cognitive aging and onset of Alzheimer's disease.

The benefits of regular physical exercise (PE) for conserving the function of the cardiovascular, musculoskeletal and nervous systems are well known. Regular PE commencing from young or middle age appears to be a necessary lifestyle change for maintaining good health in old age. Since drugs that significantly prevent age-related cognitive decline are yet to be discovered, it is vital to start PE regimen early in life when the neural reserve is still adequate, to completely avoid or at least postpone the cognitive decline. However, the amount of PE required in young or middle age to maintain healthy cognitive function in old age is yet to be ascertained.

The efficacy of intracerebral transplantation or peripheral injection of a variety of stem cells including mesenchymal stem cells (MSCs), NSCs or glial-restricted progenitors (GRPs) has been examined in animal models to improve the function of the aging brain. Stem cell therapy has been shown to mediate beneficial effects in several age-related neurodegenerative disease models. Studies revealed that the mechanism underlying a better cognitive function involved an improvement in hippocampal synaptic density mediated by BDNF. In addition to stem cell grafting approach, activation of endogenous cells in some regions of the body has promise for mediating regeneration during aging.

In conclusion, there are many anti-aging strategies in development, some of which have shown considerable promise for slowing down aging or delaying the onset of age-related diseases. From multiple pre-clinical studies, it appears that upregulation of autophagy through autophagy enhancers, elimination of senescent cells using senolytics, transfusion of plasma from young blood, neurogenesis and BDNF enhancement through specific drugs are promising approaches to sustain normal health during aging and also to postpone age-related diseases. However, these approaches will require critical assessment in clinical trials to determine their long-term efficacy and lack of adverse effects on the function of various tissues and organs.

The age-specific probability of death follows diverse, often species-specific curves. In several species, including humans, rates of mortality increase with age have been observed flattening in advanced old age. In some cases, this late-life mortality deceleration (LLMD) is sufficient to cause a levelling off or plateau in the probability of death at advanced ages. LLMD and late-life mortality plateaus (LLMPs) have been proposed to cause the respective slowing or cessation of biological ageing at advanced ages and, respectively, increase and remove the upper limits of survival in humans.

These findings have led to continuing debate on the biological meaning, magnitude, and importance of LLMDs and LLMPs. Several hypotheses and models have been proposed to explain the observation of LLMPs and LLMDs in diverse taxa, such as population heterogeneity, density effects, and evolutionary theories. In parallel, these observations have led to the development and widespread use [of demographic models, such as the Kannisto old-age-mortality model, that assume a priori the existence of LLMPs.

However, there is evidence that LLMPs can result from diverse statistical errors, such as the pooling of human cohorts, choice of mortality rate metric or time interval, and missing death certification or age-reporting errors. Furthermore, in any species with finite upper limits of life, both random and nonrandom error distributions will necessarily favour the inclusion of younger individuals amongst the oldest survivable age categories, reducing the subsequent probability of death calculated for these ages. As a result, deformation of late-life mortality by biodemographic errors may provide a general explanation of LLMDs and LLMPs.

Therefore, understanding late-life mortality patterns requires consideration of the effect of age-coding errors and whether the late-life patterns of mortality rates in humans may represent combined outcomes of measurement and sampling errors. Here, it is revealed how diverse demographic errors deform the age-specific mortality curve and the hazard rate, causing LLMDs and LLMPs in the absence of other effects. In humans, the error rate of demographic sampling, completeness of birth and death records, and development and income indicators all predict the magnitude of LLMD. Correcting for these factors eliminates LLMDs and LLMPs, suggesting these patterns are caused by sampling and measurement error and not by biological or evolutionary factors.

In mammals, generation of new neurons (neurogenesis) is mainly limited to early childhood and occurs in adulthood only in a few regions of the forebrain. One such exception is olfactory neurons, which develop from stem cells via several intermediate stages. "The production of these neurons diminishes with advancing age. In our recent study we wanted to find out the cellular basis and what role stem cells play in the process. Our approach utilised what are known as confetti reporters to perform lineage tracing: In mouse brains, we induced individual stem cells and all their descendants - called clones - to light up in a specific colour. In this way, we could distinguish clones over time by the different colours."

"In the next step, we compared clones found in young and older mice to find out what contribution individual stem cells and intermediates make to the neurogenesis of mature olfactory cells. We compared the confetti measurements with several mathematical models of neurogenesis. We found that the ability of self-renewal declines in old age, especially in certain intermediate stages called transit amplifying progenitors. In addition, analysis showed that asymmetric cell division and quiescence of stem cells increased in older mice. That means that fewer cells differentiate into olfactory cells in old age as they tend to remain in the stem cell pool and become less active. Therefore, the production comes to a halt."

This study is a large-sample cross-sectional study. Based on the comprehensive blood test and analysis, the ageing biomarkers were screened to establish the male and female biological age assessment formulas. From the perspective of prevention, the assessment of ageing is only the starting point. The purpose of the assessment is to screen out high-risk individuals, implement targeted interventions for high-risk individuals to achieve anti-ageing and longevity, and reduce the possibility of chronic diseases caused by ageing. Therefore, on the basis of assessing ageing, we explored the elimination of ageing biomarkers by double filtration plasmapheresis.

Assessing ageing is only the beginning of solving the problem of ageing. The anti-ageing intervention program for high-risk individuals is the end point. In clinical treatment, double filtration plasmapheresis has been approved for the treatment of critically ill patients, but its use in disease prevention has not been reported. This study explored the potential application of double filtration plasmapheresis in anti-ageing. Nine hundred and fifteen subjects underwent biological age assessment before and after intervention. The results confirmed that the biological age of males and females decreased by 4.47 years and 8.36 years after intervention. It is suggested that double filtration plasmapheresis technology might have potential application value in anti-ageing.

Dermal fibroblasts are specialized cells deep in the skin that generate connective tissue and help the skin recover from injury. Some fibroblasts have the ability to convert into fat cells that reside under the dermis, giving the skin a plump, youthful look and producing a peptide that plays a critical role in fighting infections. Researchers have now discovered the pathway that causes this process to cease as people age.

Don't reach for the donuts. Gaining weight isn't the path to converting dermal fibroblasts into fat cells since obesity also interferes with the ability to fight infections. Instead, a protein that controls many cellular functions, called transforming growth factor beta (TGF-β), stops dermal fibroblasts from converting into fat cells and prevents the cells from producing the antimicrobial peptide cathelicidin, which helps protect against bacterial infections.

"Babies have a lot of this type of fat under the skin, making their skin inherently good at fighting some types of infections. Aged dermal fibroblasts lose this ability and the capacity to form fat under the skin. Skin with a layer of fat under it looks more youthful. When we age, the appearance of the skin has a lot to do with the loss of fat." In mouse models, researchers used chemical blockers to inhibit the TGF-β pathway, causing the skin to revert back to a younger function and allowing dermal fibroblasts to convert into fat cells. Turning off the pathway in mice by genetic techniques had the same result.

The aging process and age-related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain-derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet-induced and genetic models.

Here we examined the efficacy and safety of a built-in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle-aged mice. The single rAAV vector harbors two cassettes, one expresses human BDNF driven by a constitutive promoter, the other expresses a microRNA targeting BDNF under the control of agouti-related peptide (AGRP) promoter that is activated by weight loss and fat depletion. This dual-cassette vector mimics the body's natural feedback system to achieve autoregulation of the transgene.

Twelve-month-old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging-associated metabolic declines characterized by: preventing aging-associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety-like and depression-like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.