Fight Aging! Newsletter, December 31st 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn’t work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Regulator of Inflammation TGF-β1 Contributes to Muscle Atrophy in Aging
  • Investigating Sex Chromosome Effects on Longevity in Mice
  • Alternative Oxidase Gene from Sea Squirts is Used to Partially Bypass a Form of Mitochondrial Dysfunction in Mice
  • A Selection of Recent Research into Biomarkers of Aging
  • The Immune System Culls Harmful Senescent Cells, and Aging is Accelerated when that Function is Impaired
  • In Vivo Cell Reprogramming as a Path to Rejuvenation
  • Reviewing Quality Control of Protein Synthesis in the Context of Aging and Longevity
  • A Mechanism by which Gut Bacteria Mediate the Effects of Dietary Fiber on Inflammation
  • Summarizing the Recent Debate Over Adult Neurogenesis in Humans
  • A Review of Presently Popular Approaches for the Construction of Therapies to Slow or Reverse Aging
  • Evidence for a Human Late Life Mortality Plateau is an Illusion Arising from Bad Data
  • The Supply of New Olfactory Neurons Diminishes with Age
  • Plasmapheresis Reduces Age-Related Biomarkers in Blood
  • TGF-β is Involved in the Loss of Fat and Bacterial Defenses in Aging Skin
  • BDNF Gene Therapy Slows Measures of Metabolic Aging in Mice

Regulator of Inflammation TGF-β1 Contributes to Muscle Atrophy in Aging

Inflammatory signaling disrupts all sorts of normal tissue functions. In the short term this is usually beneficial; inflammation is a necessary part of wound healing, defense against pathogens, and even destruction of errant cells. It is required to mobilize the immune system and coordinate the activities of various classes of immune cell with those of other cell populations. Unfortunately inflammation becomes chronic in later life, and the constant inflammatory signaling – and cellular reactions to that signaling – degrades normal function and produces lasting damage as a result. This particularly noteworthy when it comes to loss of regenerative capacity and generation of harmful fibrosis.

Chronic inflammation in aging and disease has long been a topic of interest for the research community, and a great deal of effort has been put into trying to understand the fine details of inflammation and means to control it. The newfound acceptance of the past few years that accumulation of senescent cells and growth in their potent inflammatory signaling is a significant cause of degenerative aging has only reinforced this part of the field.

“Inflammatory signaling” is, however, a very broad category. The processes of inflammation are very complicated, as is true of any situation in which multiple types of cell are interacting with one another. It is rarely the case that researchers can point to any one protein and say that more of it is always a bad thing. Context and timing and location all matter. Further, many inflammatory signal proteins have roles other than that related directly to the immune system – evolution is very much in favor of promiscuous reuse of component parts that happen to be lying around. TGF-β1 is a good example. It can increase or decrease inflammatory activity in specific contexts, and while it is definitely a prominent part of the problem of chronic inflammation in later life, it cannot simply be suppressed without unwelcome side-effects, the loss of activities that are still beneficial even in the context of a damaged immune system.

It is challenging (meaning expensive and slow) to unravel the complexity of metabolism, even in the context of a well researched single protein, in order to arrive at therapies that override dysfunction in some way. This is precisely why we should avoid messing with metabolism, investing in this process of trying to find overrides in a poorly understood, complex system. Instead, the focus should be on examining the root causes of this dysfunction. Find ways to repair or remove the cell and tissue damage that leads to chronic inflammation and the pathological state of the aged immune system. When damage is meaningfully repaired, then a complex system will revert on its own to a more functional, youthful state.

Central Role of Transforming Growth Factor Type Beta 1 in Skeletal Muscle Dysfunctions: An Update on Therapeutic Strategies

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.

Investigating Sex Chromosome Effects on Longevity in Mice

The well-known difference in longevity between genders, in which females live longer than males, is not peculiar to our species. It is present in most gendered species examined to date, which strongly suggests that these differences in the pace of aging arise quite robustly from the interaction of evolutionary pressures with gender roles in mating and reproduction. Males can achieve reproductive fitness by investing resources into mating sooner rather than later, while for females greater fitness arises through investing resources to retain the capacity to mate successfully over time. The male candle burns brighter and less long. This is an overly simple summary of a complicated and much debated area of research, however.

The research reported here is an interesting addition to the literature on this topic. Some years ago the scientific community engineered mouse lineages with a mix of sex chromosomes and gonads, so as to obtain physically male mice with female sex chromosomes, and vice versa. Most mammals have two sex chromosomes, X and Y, producing XX chromosome females and XY chromosome males. This allows researchers to split out the contribution of sex chromosomes versus gonads for most gender differences, and determine relative level of importance. Here the researchers have chosen to focus on differences in the pace of aging, running a lifespan study on mice with different combinations of sex chromosomes and gonads. Unsurprisingly, both female sex chromosomes and gonads provide a modest survival advantage. The sex chromosome effect is larger, however, which might not be the expected outcome for many observers.

This is all, of course, a matter of purely scientific interest rather than a matter of relevance to the future of aging. The introduction of rejuvenation therapies will make any of the existing disparities in aging irrelevant, and the mechanisms that produce gender differences in longevity have no role to play in the development of rejuvenation therapies. These therapies will work through repair of the molecular damage that causes aging, which is exactly the same in both genders. When it becomes possible for everyone to use medical science to live decades longer in good health, few people will care about evolved difference that might add or subtract a few years from human life spans.

Female XX sex chromosomes increase survival and extend lifespan in aging mice

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.

Alternative Oxidase Gene from Sea Squirts is Used to Partially Bypass a Form of Mitochondrial Dysfunction in Mice

Researchers recently demonstrated that they could rescue a form of mitochondrial dysfunction in mice by importing a gene from a sea squirt species. This is particularly interesting in the context of aging, as it appears to be possible to use this approach to work around any sort of damage to complexes III and IV in the mitochondrial electron transport chain (ETC). Every cell is equipped with a herd of mitochondria that act as generators, packaging the chemical energy store molecules used to power the cell. The ETC is central to this function.

The protein complexes that make up the ETC are made up of a mix of proteins encoded in both nuclear DNA and mitochondrial DNA. Dramatic mutations, such as deletions, can lead to mitochondria that function poorly or not at all. When this occurs during embryonic development, the result is either death or a much shortened and more uncomfortable life. When a mutation in mitochondrial DNA occurs in a single cell in an adult, on the other hand, as the result of the sort of random damage that takes place constantly in cells, it is usually either promptly repaired or the damaged mitochondrion is recycled.

Some forms of damage can lead to a more insidious result, however, producing a mitochondrion that is both dysfunctional and able to evade quality control mechanisms. Since mitochondria replicate like bacteria, on the rare occasions on which this happens, a cell is quickly overtaken by broken mitochondria. The cell becomes broken itself, exporting harmful oxidative molecules into the surrounding tissue and bloodstream. This has a range of undesirable downstream consequences, one of which is the creation of oxidized lipids that contribute to atherosclerosis.

The SENS Research Foundation’s approach to this problem is gene therapy to place backup copies of mitochondrial genes into the better protected cell nucleus. Thus even given damage to mitochondrial DNA, there is still a supply of proteins to ensure that the ETC functions correctly. The paper here represents an alternative but conceptually similar approach, adding novel protein machinery from other species that can do some of the work of ETC protein complexes. It only fixes a portion of the lost functionality in this case, but is nonetheless most intriguing. The researchers are focused on mitochondrial disease, but it would be very interesting to repeat their approach in the context of aging and mitochondrial function.

Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

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.

A Selection of Recent Research into Biomarkers of Aging

If the research community had a reliable, low-cost method of quickly assessing biological age, the burden of damage and dysfunction, a measure that is distinct from chronological age, then progress towards rejuvenation therapies might be accomplished more rapidly. At present the only reliable way to determine whether or not a given therapy produces a slowing of aging or rejuvenation is to run expensive, slow life span studies in mice. Even when taking the approach of starting the study with old mice, this is still quite a lengthy undertaking. Being able to apply a putative rejuvenation therapy to mice (or dogs, or non-human primates, or people) and then a few weeks later run a brief test to see how well it did would revolutionize the pace of progress.

Based on the past decade of work on biomarkers of aging, it seems plausible that a diverse weighted combination of measures will eventually prove to be good enough to greatly improve the economics of development for rejuvenation therapies. That good enough combination has yet to be established robustly, however. The various epigenetic clocks are promising, but not yet actionable, as researchers cannot say how exactly these clocks relate to the specific forms of molecular damage that cause aging. If the aggregate measure is higher or lower or unchanged following a given treatment, what does that mean? There is as yet no good answer to that question, and the answers will no doubt differ by class of therapy. Different biomarkers will react differently to various forms of biological repair. The same issue also applies to the other approaches beyond epigenetic measures.

Meanwhile, researchers continue to add new biomarkers and new combinations of existing biomarkers to the growing stack. The number of possible options grows on a month by month basis, but it may be that, at this stage, more effort should go towards calibrating the behavior of an existing biomarker approach, following use of interventions to slow or reverse aspects of aging, rather than continuing to pile additional markers onto the heap.

Age is more than just a number: machine learning may be able to predict if you’re in for a healthy old age

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 detect age-related differences in DNA from blood

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.”

Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloid-β Are Strongly Associated With Healthy Aging in the Oldest Old

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.

The Immune System Culls Harmful Senescent Cells, and Aging is Accelerated when that Function is Impaired

Cellular senescence is one of the causes of aging. Cells become senescent in response to a variety of circumstances, the most common of which is when a somatic cell reaches the Hayflick limit on replication. Senescence also arises as a result of damage, to shut down cells that might become cancerous. Senescent cells cease to replicate, issue inflammatory signals that attract immune cells to destroy them, and usually self-destruct via programmed cell death mechanisms in any case. The problem with cellular senescence arises from the tiny fraction of senescent cells that evade destruction and linger, polluting surrounding tissue with inflammatory and other signals that evolved for short-term benefit only. When present over the long term, the signals secreted by even a comparatively small number of senescent cells will significantly degrade tissue structure and function, disrupt regeneration, and produce chronic inflammation. This accelerates the development and progression of near all common age-related diseases.

The targeted destruction of senescent cells has been well proven as a rejuvenation therapy in mice in recent years, and human trials are underway for the first senolytic drugs capable of achieving this goal. These initial drugs will be improved upon considerably in the years ahead, as they have side-effects, and only destroy half of the senescent cell burden in some tissues at best, but I expect them to nonetheless produce sizable and broad benefits in older people. Senolytic treatments are a form of repair, clearing away harmful cells that actively maintain a a state of greater dysfunction.

While forging ahead to bring benefits to tens of millions of patients as soon as possible is absolutely the right thing to be doing, there yet remains a great deal to accomplish and investigate as the field expands. On the clinical side of the fence, there are no good commercial assays that quickly and cost-effectively show senescence levels in human tissue, for example. On the scientific side of the fence, it is far from clear as to whether there exist significantly different classes of senescence with meaningful differences in activity and vulnerability to particular senolytic mechanisms. Cataloging past a handful of biomarkers and tissues has barely started. There is also the topic of today’s paper, which is the degree to which the presence of lingering senescent cells increases with age because the immune system becomes compromised and falters in its surveillance. Killing senescent cells is a lot easier than restoring the immune system to youthful function, but when that goal is achieved, to what degree will senescence be purged from tissues? The open access paper here is an interesting first attempt to look at the size of this effect.

Impaired immune surveillance accelerates accumulation of senescent cells and aging

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 against senescent cells varies between 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.

In Vivo Cell Reprogramming as a Path to Rejuvenation

Reprogramming of ordinary somatic cells into induced pluripotent stem cells (iPSCs) capable of generating any cell type is very much a going concern these days. The first cell therapies based on the transplantation of patient-matched cells derived from iPSCs are entering trials. More recently, however, researchers have been experimenting with the more radical idea of reprogramming cells in situ, in tissues. At first glance (and later consideration) this seems enormously risky, a fast path to cancer. Yet in mouse studies it appears, at least initially, to be quite beneficial. It will take a great deal more data to overcome skepticism about the cancer risk, but it seems there is a faction of researchers ready to work towards that goal.

Equally intriguing is the evidence for reprogramming to reset some of the markers of cell and tissue age, such as mitochondrial dysfunction. A complete catalog of what is fixed and what is not fixed by this process, and which of those items are more or less important than the others, has yet to be assembled. This is a comparatively recent development in the field, and, accordingly, comparatively little exploration has taken place. Will reversal of aspects of aging hold up when cells are put back into tissue? Which of the changes are lasting versus transient? A great deal of work lies ahead.

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.

Reviewing Quality Control of Protein Synthesis in the Context of Aging and Longevity

Both quality control and pace of production of proteins in cells are linked to aging. When comparing species and lineages with different life spans, long-lived mutants of short-lived species such as nematode worms exhibit a slower rate of protein synthesis. The same is true in yeast. Equally, the long-lived naked mole-rat exhibits highly efficient quality control in protein synthesis when compared to short-lived rodent species of a similar size. It is also the case that for any given individual, the quality control of protein synthesis becomes worse with age, and this – like stochastic mutation of DNA, and for similar reasons – is thought to be a contributing factor in the progression of degenerative aging. That said, where exactly it sits in the long chains of cause and effect between first cause of aging and final downstream outcome of aging is up for debate.

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.

A Mechanism by which Gut Bacteria Mediate the Effects of Dietary Fiber on Inflammation

Dietary fiber is known to reduce chronic inflammation; the modest but reliable degree to which it does so is well studied. In recent years researchers have been turning their attention to the diverse microbes of the gut in order to understand how this and other dietary effects on the immune system and tissues are mediated. Some attention has been given to the production of butyrate by gut bacteria involved in digesting fiber, for example. Researchers here find an analogous mechanism in the bacterial production of propionate from fiber, and make some inroads into understanding how exactly it functions to reduce inflammation.

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.”

Summarizing the Recent Debate Over Adult Neurogenesis in Humans

Does the adult brain produce and integrate new neurons into its neural circuits, in a process known as neurogenesis? Near all of the evidence for this process to take place in adults has been established in mice, and over the past year a few new studies have suggested that this process doesn’t in fact occur in humans. This is something of shock to the research community, as a fair number of regenerative medicine projects are progressing under the hope that existing neurogenesis can be increased in scope and pace, in order to repair and restore the aged brain to greater degrees than presently occurs naturally. If the neurogenesis so well characterized in mice doesn’t exist in humans, then those projects will all fail. It is an important topic, but we shouldn’t expect resolution of this debate to arrive in the near term. Conflicting data that is so carefully produced and so directly opposed tends to require years of work to resolve, particularly when human tissues are vital to the end goal.

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.”

A Review of Presently Popular Approaches for the Construction of Therapies to Slow or Reverse Aging

This open access review paper surveys the present major areas of interest in the development of therapies expected to slow or reverse aging to some degree. Of the well-funded and popular lines of research and development, only one is unequivocally a form of rejuvenation, the new field of senolytic therapies able to selectively destroy senescent cells. Of the others noted, only stem cell therapies and possibly upregulation of neurogenesis have the potential to become rejuvenation therapies, at the point at which researchers become able to reliably replace damaged cell populations with fresh, functional cell populations. That point has not yet been reached.

The rest of the items, which account for the majority of present research efforts in the treatment of aging, are either (a) the well known lifestyle factors such as exercise and calorie restriction, or (b) attempts to override undesirable cell behavior without actually fixing the damage and dysfunction that underlies that altered behavior in aging. The scope of potential benefits is thus limited; trying to keep a damaged machine running by tinkering with the controls is a challenging way to eke out only incremental gains. The future that must come to pass, if we are to see significant extension of human life span in the decades ahead, is one in which the fields of rejuvenation research not listed in this paper, the other portions of the SENS damage repair agenda beyond senolytics, must become as large and well-funded and popular as senolytics is today.

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 improved 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.

Evidence for a Human Late Life Mortality Plateau is an Illusion Arising from Bad Data

Mortality rises with age. In fact the very definition of aging is that it is a rise in mortality rate due to intrinsic causes, the accumulation of unrepaired damage and subsequent systems failure. Some years ago it was quite robustly established that, after a certain point, aged flies stop aging in this sense. Their mortality rates remain at a very high plateau, and do not further increase over time. Since then, researchers have crunched the numbers and debated back and forth over whether or not human demographic data shows any signs of a similar phenomenon. The challenge is the sparse, poorly gardened nature of the demographic data for people who pass a century of age. The authors of the paper noted here argue that all of the past evidence for a human mortality plateau emerged precisely because the data is problematic, and that systemic issues with data quality will tend to produce this apparent result.

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.

The Supply of New Olfactory Neurons Diminishes with Age

Stem cell populations maintain tissues in large part by providing a supply of new daughter cells to replace losses and repair damage. This supply diminishes with age, however, as stem cell populations become ever less active. This results from some mix of damage to the stem cells themselves and the more general damage of aging, accompanied by altered signaling as a reaction to that damage. The consensus is that stem cells have evolved to become less active in a damaged environment in order to diminish risk of cancer, but this is by no means settled, given that various approaches to force stem cells into greater activity appear to cause far less cancer than expected.

The decline in stem cell function is perhaps best studied in muscle tissue, but the phenomenon is most likely present in all tissues, each supported by its own varieties of stem cell. Here, researchers painstakingly demonstrate that neural stem cells falter in their delivery of olfactory neurons. The necessary functional tissue will thus deteriorate, and this contributes to the failing sense of smell observed in older individuals.

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.”

Plasmapheresis Reduces Age-Related Biomarkers in Blood

Researchers here demonstrate that the blood filtration methodology of plasmapheresis results in a temporary reduction in markers associated with aging in the bloodstream. Whether or not this is helpful is another question, and that was not assessed here. Frequently repeated plasmapheresis is an expensive proposition at the present time, far too costly to be worth it for any minor gain. It is, however, an interesting idea in the context of work on parabiosis, the linking of circulatory systems between an old and young animal, where at least one group seems convinced that benefits to the older animal result from dilution of harmful signals in old blood rather than delivery of helpful signals from young blood.

Setting aside the usually considered markers in old blood, what I would consider to be better and more proven targets for filtration based approaches include exhausted and senescent T cells, and molecular waste such as amyloid-β, which exists in the blood in equilibrium with its presence in the brain. It has been shown that clearing it from blood can produce benefits in Alzheimer’s disease. Other possible targets include the various forms of oxidized lipid that contribute to atherosclerosis and other age-related issues.

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.

TGF-β is Involved in the Loss of Fat and Bacterial Defenses in Aging Skin

TGF-β is a problematic protein that is involved in the regulation of chronic inflammation and many other processes important in aging. Unfortunately, presently available means of suppressing TGF-β activity have potentially serious side-effects, as TGF-β has important functional roles in many tissues, even in later life, while it is at the very same time causing a broad set of problems. This is a challenge found in many places in medicine: it is rarely enough to be able to globally increase or diminish the activity of a given protein, as its relationships with the operation of cellular metabolism are usually quite complicated. Here, researchers show that, on top of all of the other issues laid at the feet of TGF-β, it blocks the ability of fibroblasts in aging skin to transform into fat cells and generate antibacterial defenses.

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.

BDNF Gene Therapy Slows Measures of Metabolic Aging in Mice

Researchers here test a gene therapy that mimics the normal regulatory mechanisms governing BDNF expression in the hypothalamus, enhancing BDNF activity only when it is called for. In aging mice, this slows the expected decline of metabolism, as measured by a variety of metrics and markers. As a basis for a human enhancement therapy, this is intriguing, but not a near term prospect. I think we are at present quite a long way removed from a world of reliable, widely available gene therapies targeted to the brain, even under the most aggressive timelines.

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.

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