Fight Aging! Newsletter, June 10th 2019

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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  • A Novel Approach to the Construction of Thymus Organoids
  • More Evidence for Cellular Senescence of β Cells to Drive Type 2 Diabetes
  • Progress Towards Blocking Alternative Lengthening of Telomeres in Cancer
  • Senolytic Therapies to Clear Senescent Cells Should Benefit Cancer Patients
  • Restoration of Impaired Cellular Housekeeping in Intestinal Stem Cells in Aging Flies Improves Function and Extends Life
  • Unity Biotechnology Broadens its Pipeline to Include Klotho
  • Telomerase Gene Therapy Treats Neurodegeneration in Mice
  • A Surprisingly Simple Stem Cell Therapy Restores Sense of Smell in Mice
  • Enzymes of Xenobiotic Metabolism and Variation in Human Longevity
  • Impaired Mitophagy and Mitochondrial Function in Alzheimer's Disease
  • MiR-135a-5p as a Target to Induce Greater Neurogenesis
  • Exosomes in Harmful Senescent Cell Signaling
  • Towards Targeting the Toxins of Oral Bacteria in the Alzheimer's Brain
  • Targeting GATA Transcription Factor to Upregulate Autophagy
  • Deterioration of Immune Responses in the Aged Gut in Mice is Reversed via Transplantation of Youthful Gut Microbes

A Novel Approach to the Construction of Thymus Organoids

The thymus is a small but important organ; it is where thymocytes originally generated in the bone marrow mature to become T cells of the adaptive immune system. Unfortunately the active tissue of the thymus is slowly replaced by fat over the course of later life, and the supply of new T cells dwindles. This is a significant contributing cause of the age-related decline in immune function. Lacking reinforcements and replacements, the adaptive immune system becomes cluttered with senescent, exhausted, overspecialized, and just plain broken cells. It becomes overly active and inflammatory, but at the same time ineffective. It progressively becomes ever less competent when it comes to destroying cancerous and senescent cells, and defending against pathogens.

This is all well recognized, and over the years a range of efforts to regenerate the thymus have been undertaken. As of yet few have progressed much further than animal studies in mice. Recombinant KGF, which works quite well to enlarge the thymus in mice and non-human primates, failed utterly in a human trial, showing absolutely no effect. More recently, the staff at Intervene Immune have been combining some of the older and unreliable methods, such as use of growth hormone, into human tests of thymic regrowth. All of these approaches, and a few others, largely boil down to ways to upregulate FOXN1, the master controlling gene of thymic growth and T cell maturation activity. The most compelling studies in mice have been those in which FOXN1 expression was manipulated directly, and we might suspect that any therapy that grows a thymus, but fails to keep FOXN1 levels high going forward, will also fail to make a large and lasting impact on T cell generation. The thymus must be active, not just larger, and FOXN1 expression declines with age.

Tissue engineering offers an intriguing approach to the problem of the thymus, bypassing a lot of the hard work inherent in trying to manipulate expression of a given gene. (Of course replacing it with hard work of a different sort). Functional thymus tissue can be grown in small amounts, lacking a network of small-scale blood vessels, but able to be transplanted. Since thymocytes home to the thymus, thymic tissue located almost anywhere in the body will still be capable of doing its job, in principle. This has been demonstrated by implanting thymus organoids into lymph nodes, an approach being commercialized by Lygenesis. As the results here show, however, success still depends on building a suitably resilient tissue that will last for a long time following transplantation.

Gene Modification and Three-Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches

Many research groups have primarily focused on finding possible strategies to rejuvenate the thymus and have developed promising therapeutic approaches. However, few molecules and genes such as KGF, IL-22, IL-7, and Foxn1 have been identified as key players of the mechanistic pathway for endogenous thymic regeneration. Growth factors and hormone therapies were also explored in order to restore age-related or injury-related thymic degeneration, but, despite encouraging results, they have short-term effects and/or require a recurrent administration, which is complicated by their toxic effects on other tissues and organs.

Thymus transplantation represents another promising alternative to complement bone marrow transplantation or to treat congenital thymic anomalies, but T-cell reconstitution following thymus grafting is frequently incomplete and transient, complicated by a skewed T-cell receptor repertoire and an increased occurrence of autoimmunity.

The field of tissue engineering has put considerable efforts into the development of materials and techniques for the in vitro generation of tissues of clinical relevance. The major challenge for tissue engineering is to successfully recreate the complexity of the 3D structure of the thymic microenvironment and to fully rebuild the composition and organization of the thymic extracellular matrix (ECM). The use of thymic organoids formed by human thymic epithelial cells (TECs) and fibroblasts as well as seeding TECs into matrigel or other 3D biocompatible systems has been shown to promote a transient thymopoiesis in vivo. The use of de-cellularized thymic tissue has been suggested to overcome these limitations and has shown promising results in mouse models. However, the use of decellularized tissues, obtained from cadavers or patients undergoing cardiothoracic surgery, limits the applicability of such approaches to the availability of donors.

The use of postnatal TECs for thymic regeneration has revealed challenging because of the loss of thymopoietic function of TECs after in vitro culture. To avoid the use of embryonic TECs or induced pluripotent stem cell derived TECs, attempts have been made by combining mature TECs with different 3D systems for developing functional mini-thymus units. Several studies have been focused on the investigation of ideal biomaterials for human applicability, which need to be biocompatible, biodegradable, and easily detectable with imaging techniques regularly used in standard clinical practice. Collagen has been widely used in tissue engineering because it can be assembled in fibers closely reproducing the chemical and morphological characteristics of those present in soft tissues. Therefore, the production of collagen porous biomatrix could make this biomaterial suitable for the generation of thymic constructs.

Hence, we developed a potentially new therapeutic strategy that foresees transplantation of biomimetic scaffolds, mimicking the thymic ECM organization, obtained by seeding adult murine TECs and expanding them into 3D collagen type I scaffolds. In order to use postnatal TECs for the generation of transplantable thymic structure, we sought to induce a short-term expression of Oct4, a transcription factor involved in the maintenance or induction of pluripotency in embryonic cells, to obtain transient partial de-differentiation and promote their expansion. To create a physiologically relevant microenvironment to seed TECs, we tested 3D collagen type I scaffolds crosslinked with different amounts of 1,4-butanediol diglycidyl ether (BDDGE).

Here, we show that 3% BDDGE collagen-based scaffolds seeded with gene-modified TECs and transplanted subcutaneously in athymic nude mice were perfused and colonized by small new blood vessels and were able to sustain TEC survival in a 3D microenvironment. However, further improvement of the 3D scaffold composition is required to obtain long-term in vivo persistence of organoids that could allow the development of this approach for future clinical applications.

More Evidence for Cellular Senescence of β Cells to Drive Type 2 Diabetes

Recently, researchers have demonstrated that senescence of pancreatic β cells is important in both the autoimmunity of type 1 diabetes and the metabolic dysfunction of type 2 diabetes. This was very surprising in the first case, less so in the second, since type 2 diabetes emerges more readily in older individuals. The specific mechanisms by which increased cellular senescence arises in the pancreas is probably different in each case, but the use of senolytic treatments to clear senescent cells has produced significant benefits in animal models of both conditions. This adds to the many other conditions in which targeted removal of senescent cells is a viable therapy.

Here, researchers outline more evidence for an important role for cellular senescence in type 2 diabetes. It is compelling. It has to be said that s time moves on, senolytic therapies look ever more like a panacea of sorts, capable of improving near any condition where incidence is correlated with aging, and even a few where that is not the case. Given that the first senolytic drugs and supplements with well-explored pharmacological safety data, good results in mouse studies, and an emerging set of human trial results are both very cheap and readily available given a little investigation of the options, I fully expect that patients will start to take matter into their own hands long before companies can obtain regulatory approval for the first therapies in their senolytic pipelines.

Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes

Type 2 diabetes (T2D) is an age-related disease characterized by a decrease of β cell mass and function, representing a failure to compensate for the high insulin demand of insulin-resistant states. Yet, the role of aging as it pertains to pancreatic β cells is poorly understood, and therapies that target the aging aspect of the disease are virtually non-existent. For many years, β cells can compensate for increased metabolic demands with increased insulin secretion, keeping hyperglycemia at bay. This compensation may be limited by the age-related decline in β cell proliferation seen in rodents. This deficiency in proliferative response to increased demand may arise partly from the accumulation of senescent β cells.

Cellular senescence is a state in which cells cease to divide but remain metabolically active with an altered phenotype. There are no universal markers of senescence, and the markers that exist are not consistent in every senescent tissue. p16Ink4a, a cyclin-dependent kinase inhibitor encoded by the Cdkn2a locus, has been identified as both marker and effector of β cell senescence. An increase in p21, another effector of cellular senescence, is thought to mark the entry into early senescence leading to increased p16Ink4a expression, which then maintains senescence, resulting in the expression of the senescence-associated secretory phenotype (SASP).

SASP profiles differ with tissue type and can include soluble and insoluble factors (chemokines, cytokines, and extracellular matrix affecting proteins) that affect surrounding cells and contribute to multiple pathologies. With age, accumulation of dysfunctional senescent β cells likely contributes to impaired glucose tolerance and diabetes. Yet, the specific contribution of β cell aging and senescence to diabetes has received little attention, and the specific SASP profile of β cells remains to be determined.

We generated a β cell senescence signature and found that insulin resistance accelerates β cell senescence leading to loss of function and cellular identity and worsening metabolic profile. Senolysis (removal of senescent cells), using either a transgenic INK-ATTAC model or oral ABT263, improved glucose metabolism and β cell function while decreasing expression of markers of aging, senescence, and SASP. Beneficial effects of senolysis were observed in an aging model as well as with insulin resistance induced both pharmacologically (S961) and physiologically (high-fat diet). Human senescent β cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of β cells as a preventive and alleviating strategy for T2D.

Progress Towards Blocking Alternative Lengthening of Telomeres in Cancer

Well, this is promising news. Researchers have found that inhibition of FANCM activity is a potential point of intervention to shut down alternative lengthening of telomeres (ALT) in cancer. This goal is one half of the ultimate cancer therapy, a form of treatment that is (a) capable of shutting down all forms of cancer, without exception, where (b) cancers cannot evolve resistance to its mechanisms, and (c) it requires little to no expensive, time-consuming adaptation for delivery to different cancer types. The other half is a method of blocking the ability of telomerase to lengthen telomeres, and several research groups have made inroads towards that goal. Both are needed in combination, since ALT cancers might evolve to become telomerase cancers, and vice versa.

Why would this work? All cancers absolutely require some method of lengthening telomeres in order to support their rampant growth, and - so far as we know - this means either telomerase or ALT. Telomeres are caps of repeated DNA sequences at the end of chromosomes, and a little of their length is lost with each cell division. They are a part of the counting mechanism that enables the Hayflick limit on cell division; when telomeres become short, a cell ceases to replicate and self-destructs. Only with continued lengthening of telomeres can a cell keep on dividing indefinitely. Without this, a cancer would wither away.

You might recall that the SENS Research Foundation team made an attempt to find ALT-blocking small molecules a couple of years ago as a part of the OncoSENS research program, supported by philanthropic crowdfunding. Unfortunately that failed, as small molecule screens sometimes do. It is a roll of the dice, consulting the vast compound databases in ways that are intended to maximize the odds. With the new results here, now perhaps work on the ALT side of the ultimate cancer therapy has a chance to forge ahead once more. A very positive development, for all of our personal futures.

New study reveals an unexpected survival mechanism of a subset of cancer cells

Embedded at the end of chromosomes are structures called "telomeres" that in normal cells become shorter as cells divide. As the shortening progresses it triggers cell proliferation arrest or death. Cancer cells adopt different strategies to overcome this control mechanism that keeps track of the number of times that a cell has divided. One of these strategies is the alternative lengthening of telomeres (ALT) pathway, which guarantees unlimited proliferation capability. Now, a research group has discovered that a human enzyme named FANCM (Fanconi anemia, complementation group M) is absolutely required for the survival of ALT tumor cells.

Previous studies have shown that a sustained physiological telomere damage must be maintained in these cells to promote telomere elongation. This scenario implies that telomeric damage levels be maintained within a specific threshold that is high enough to trigger telomere elongation, yet not too high to induce cell death. "What we have found is that ALT cells require the activity of the FANCM in order to prevent telomere instability and consequent cell death. When we remove FANCM from ALT tumor cells, telomeres become heavily damaged and cells stop dividing and die very quickly. This is not observed in tumor cells that express telomerase activity or in healthy cells, meaning that is a specific feature of ALT tumor cells."

FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops

Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.

Senolytic Therapies to Clear Senescent Cells Should Benefit Cancer Patients

It is well known that the present dominant approaches to cancer therapy - meaning toxic, damaging chemotherapy and radiotherapy, only slowly giving way to immunotherapy - produce a significant burden of senescent cells. Indeed, forcing active cancer cells into senescence is the explicit goal for many treatments, and remains an aspirational goal for a large fraction of ongoing cancer research. Most senescent cells self-destruct, or are destroyed by the immune system, but some always linger - and more so in older people, due to the progressive incapacity of the immune system. An immune system that becomes ineffective in suppressing cancer will be similarly ineffective when it comes to policing tissues for senescent cells.

An increased burden of lingering senescent cells is a good deal better than progressing to the final stages of metastatic cancer, that much is true, but those who undergo chemotherapy understand that it is the second worse option on the table. It has a significant cost, even when completely successful. Cancer survivors may lose as much as a decade of life expectancy, and have a higher risk of suffering most of the other chronic diseases of aging. These consequences are most likely due to the presence of additional senescent cells generated by the treatment, over and above those produced over the course of aging.

The open access paper here provides supporting evidence for (a) the presence of senescent cells following radiotherapy to be harmful to patients, and (b) the removal of those errant cells to be beneficial, reversing the harms done. Senescent cells are in many ways the ideal type of damage to occur during aging: their inflammatory secretions actively maintain a harmful state of cellular metabolism in the surrounding tissue, and that stops the moment they are destroyed. Destruction is far easier to achieve than repair of structures or delivery of replacement parts, and this is perhaps one of the reasons why senolytic therapies to remove senescent cells are the first form of rejuvenation therapy from the SENS portfolio to be developed in earnest.

Restored immune cell functions upon clearance of senescence in the irradiated splenic environment

Cellular senescence is a complex phenotype observed in diverse tissues at distinct developmental stages. In adults, senescence likely acts to irreversibly prevent proliferation of damaged cells. Senescent cells appear during chronological aging, aberrant oncogene expression, and exposure to DNA damaging agents. Expression of the tumor suppressor p16INK4a increases with age in numerous mouse and human tissues and, thus, considered a reliable marker. Exposure to ionizing radiation (IR) leads to delayed increase in p16INK4a expression in mice tissues and cancer-treated patients

Senescent cells accumulate in tissues and secrete a range of cytokines, chemokines, and proteases known as the senescence-associated secretory phenotype (SASP). Why senescent cells accumulate in vivo remains unclear. One theory suggests senescence accumulates with a decline in immune functions with age. While senescent cells support wound healing, accumulation of senescent cells also appears to contribute to tumor growth and development of age-associated diseases. Significantly, genetic or pharmacological elimination of senescent cells reverses the onset of aging and associated pathologies in mice. Removing senescent cells reduces some side effects of chemotherapy and mitigate IR-induced premature aging in murine hematopoietic stem cells.

We previously observed irradiated mice developed impaired lymphopoiesis in the bone marrow, an effect both cellular nonautonomous and dependent on p16INK4a. Our current study sought to investigate whether IR-induced p16INK4a expression interfered with immune cell function. We provide evidence that exposure of mice to ionizing radiation (IR) promotes the senescent-associated secretory phenotype (SASP) and expression of p16INK4a in splenic cell populations. We observe splenic T cells exhibit a reduced proliferative response when cultured with allogenic cells in vitro and following viral infection in vivo.

Using p16-3MR mice that allow elimination of p16INK4a-positive cells with exposure to ganciclovir, we show that impaired T-cell proliferation is partially reversed, mechanistically dependent on p16INK4a expression and the SASP. Moreover, we found macrophages isolated from irradiated spleens to have a reduced phagocytosis activity in vitro, a defect also restored by the elimination of p16INK4a expression. Our results provide molecular insight on how senescence-inducing IR promotes loss of immune cell fitness, which suggest senolytic drugs may improve immune cell function in aged and patients undergoing cancer treatment.

Restoration of Impaired Cellular Housekeeping in Intestinal Stem Cells in Aging Flies Improves Function and Extends Life

In aging flies, we can consider degeneration of intestinal tissue and function as the primary cause of mortality, in much the same way as we can consider cardiovascular dysfunction as the primary cause of mortality in humans. It isn't the whole story, but it is a sizable portion of the story. Whenever reading research about intestinal function and life span in flies it is worth bearing this in mind: flies are not people, and while it is likely that similar processes operate in both species, their details and relative importance are likely different. Those preliminaries out of the way, today's open access paper is a recent example of extending life span in flies via improved intestinal stem cell function. The authors have discovered a faltering in cellular housekeeping that impairs stem cells in older flies, and which can be overridden via a suitable upregulation of the appropriate proteins.

Stem cell function in general declines with age, in all tissues. Stem cells and the cells of their supporting niche become damaged, their numbers diminished, and stem cells react in inappropriate ways to changes in the surrounding environment, such as by remaining quiescent rather than generating daughter cells to support the surrounding tissue. Numerous lines of work in regenerative medicine and the new longevity industry involve ways to put stem cells back to work, even damaged as they are. In animal studies this appears beneficial and less likely to induce cancer than was originally suspected. Present methods are not all that effective, however: we can hope that future therapies are more effective.

Of late, there has been a growing interest in the role of age-related changes in gut bacteria populations in disrupting tissue function in the intestine, generating chronic inflammation and other undesirable consequences. It is possible that gut bacteria have an influence on long-term health that is in the same ballpark as that of exercise. Thus it is perhaps interesting to compare work on this topic in flies with work on intestinal stem cells. There isn't all that much overlap at the present time, in terms of specific mechanisms examined, but little in any given tissue happens in isolation. There will be connections.

Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction

Protein homeostasis (proteostasis) encompasses the balance between protein synthesis, folding, re-folding and degradation, and is essential for the long-term preservation of cell and tissue function. This balance is perturbed in aging systems, likely as a consequence of elevated oxidative and metabolic stress, changes in protein turnover rates, decline in the protein degradation machinery, and changes in proteostatic control mechanism. The resulting accumulation of misfolded and aggregated proteins is widely observed in aging tissues. The age-related decline in proteostasis is especially pertinent in long-lived differentiated cells, which have to balance the turnover and production of long-lived aggregation-prone proteins over a timespan of years or decades. But it also affects the biology of somatic stem cells (SCs), whose unique quality-control mechanisms to preserve proteostasis are important for stemness and pluripotency.

Common mechanisms to surveil, protect from, and respond to proteotoxic stress are the heat shock response (HSR) and the organelle-specific unfolded protein response (UPR). When activated, both stress pathways lead to the upregulation of molecular chaperones that are critical for the refolding of damaged proteins and for avoiding the accumulation of toxic aggregates. If changes to the proteome are irreversible, misfolded proteins are degraded by the proteasome or by autophagy. While all cells are capable of activating these stress response pathways, SCs deal with proteotoxic stress in a specific and state-dependent manner.

While these studies reveal unique proteostatic capacity and regulation in SCs, how the proteostatic machinery is linked to SC activity and regenerative capacity, and how specific proteostatic mechanisms in somatic SCs ensure that tissue homeostasis is preserved in the long term, remains to be established. Drosophila intestinal stem cells (ISCs) are an excellent model system to address these questions. ISCs constitute the vast majority of mitotically competent cells in the intestinal epithelium of the fly, regenerating all differentiated cell types in response to tissue damage. Advances made by numerous groups have uncovered many of the signaling pathways regulating ISC proliferation and self-renewal. In aging flies, the intestinal epithelium becomes dysfunctional, exhibiting hyperplasia and mis-differentiation of ISCs and daughter cells. This age-related loss of homeostasis is associated with inflammatory conditions that are characterized by commensal dysbiosis, chronic innate immune activation, and increased oxidative stress.

ISCs of old flies also exhibit chronic inactivation of the Nrf2 homologue CncC. CncC and Nrf2 are considered master regulators of the antioxidant response. In both flies and mice, this pathway controls SC proliferation and epithelial homeostasis. Whether and how Nrf2 also influences proteostatic gene expression in somatic SCs remains unclear. Here, we show that Drosophila CncC links cell cycle control with proteostatic responses in ISCs via the accumulation of dacapo, a p21 cell cycle inhibitor homologue, as well as the transcriptional activation of genes encoding proteases and proteasome subunits. We establish that this program constitutes a transient 'proteostatic checkpoint', which allows clearance of protein aggregates before cell cycle activity is resumed. In old flies, this checkpoint is impaired and can be reactivated with a CncC activator. This limits age-related intestinal barrier dysfunction and can result in lifespan extension.

Unity Biotechnology Broadens its Pipeline to Include Klotho

Unity Biotechnology is no longer just a senotherapeutics company, focused on tackling the contribution of senescent cells to degenerative aging. The principals have now branched out into the development of therapies based on increasing circulating levels of klotho, a protein found to affect, at the very least, both kidney function and cognitive function. It was discovered some time ago in mice that raised levels of klotho modestly slow aging, while lowered levels accelerate aging. Research into klotho is actually at a very interesting point right now, with researchers close to being able to determine whether the cognitive function effects are actually mediated outside the brain, such as in the aging kidney. Declining kidney function is well known to cause cognitive decline, among the many other harms it inflicts on the body.

Unity Biotechnologies has raised an enormous amount of funding, which gives them considerable leeway to adopt new programs that fit their overall vision of tackling aging. But near every company in the growing longevity industry, at every scale of funding, can do much the same. Indeed, I think that they should. There are many more projects worthy of development than there are entrepreneurs at this time, and this will continue to be the case for years yet. The research community is littered with very interesting, promising foundations for therapies to treat aging, at or close to the point at which they can be handed over to commercial development. Most were abandoned for no better reasons than grant awarding bodies are excessively conservative, funding is constrained, and the institutions of academia and industry are largely incapable of talking coherently to one another, let alone managing a complex marketplace of hand-offs from lab to startup company. We need to do better than this.

UNITY Biotechnology, Inc. ("UNITY"), a biotechnology company developing therapeutics to extend healthspan by slowing, halting or reversing diseases of aging, and UC San Francisco (UCSF) today announced that UNITY executed an exclusive, worldwide license to UCSF intellectual property relating to the alpha-Klotho protein, a circulating factor associated with improved cognitive performance.

The alpha-Klotho protein was initially identified in mice as an "aging-suppressor" that accelerates aging when the gene encoding it is disrupted, and slows aging when the alpha-Klotho protein is over-produced. In 2017 it was reported that when the alpha-Klotho protein was injected into mice it reversed the deleterious effects of aging and age-related disease on cognition.

"Circulating levels of alpha-Klotho protein gradually decline as we age. Yet, a small percentage of the population possesses naturally elevated alpha-Klotho levels that are associated with extended healthspan, enhanced cognition and less age-associated cognitive decline. We are exploring the utility of the alpha-Klotho protein in collaboration with world-renowned researchers from UCSF, with a goal to identify a potential drug candidate to treat particular diseases of aging, including cognitive decline."

Telomerase Gene Therapy Treats Neurodegeneration in Mice

Researchers have been testing telomerase gene therapies in mice for more than a decade now, demonstrating extension of life, improved stem cell and tissue function, reduced cancer incidence, and so forth. The research results here, treating neurodegeneration in mice, are a representative example of the sort of work that has emerged in recent years. Telomerase primarily acts to lengthen telomeres, the repeated DNA sequences at the ends of chromosomes. Telomeres shorten with each cell division, a part of the mechanism determining the Hayflick limit to cell replication. Thus the general upregulation of telomerase should result in greater cell activity.

Telomerase upregulation was also widely expected to raise the risk of cancer, by putting damaged cells back to work, but so far that hasn't emerged in animal studies. If anything, the risk is reduced, perhaps due to increased activity in those parts of the immune system responsible for destroying cancerous and precancerous cells. One challenge in translating this work to human medicine is that telomere and telomerase dynamics are very different in mice and humans, and thus the balance of cancer risk versus improved regeneration may be quite different - though clearly clinical development is progressing, at Libella Gene Therapeutics and elsewhere.

Preventing accumulation of short telomeres may prevent or ameliorate brain aging by allowing stem cells to proliferate and regenerate damaged tissue. We have previously demonstrated that preventing accumulation of short telomeres through telomerase gene therapy can ameliorate the symptoms of cardiovascular disease, pulmonary fibrosis, aplastic anemia, and aging in general. Thus, to demonstrate that telomere shortening may be one of the causes of brain aging, here we studied the potential therapeutic effects of a telomerase gene therapy in ameliorating molecular signs of neurodegeneration associated with physiological mouse aging as well as in the context of the telomerase-deficient mouse model.

Our findings demonstrate that AAV9-Tert treatment can ameliorate signs of neurodegeneration with aging in wild-type mice as well as in the context of the telomerase-deficient mouse model with the presence of short telomeres. Our treatment was applied through an intravenous tail injection, and therefore, many other cell types throughout the body would be infected in addition to the cells in the brain. Improvements of health in other organs may have an impact on the brain and investigating the nature of this relationship could be interesting for future studies. Note also that we did not observe any increased incidence of cancer in the mice treated with AAV9-Tert, which matched our expectations since several other articles have demonstrated that telomerase reactivation alone does not lead to tumorigenesis in vivo.

Of note, the AAV9 serotype used here to express telomerase in the brain primarily transfects neurons and astrocytes but fails to transduce microglia. In our experimental setting, we found that less than 5% of the cells in the brain received the transgene using our vector and delivery method. Interestingly, in spite of the low transduction efficiency, we observed significant effects of AAV9-Tert gene therapy in decreasing DNA damage, increasing neurogenesis as indicated by increased doublecortin expression, as well as decreasing neuroinflammation (decreased GFAP expression). These findings suggest that even a small number of neurons transduced with Tert may increase the health of the environment and benefit cells that were not infected, for instance, through changing the secretory profile of cells. Even more benefits from telomerase gene therapy may be observed if higher transduction efficiencies are obtained.

A Surprisingly Simple Stem Cell Therapy Restores Sense of Smell in Mice

The stem cell therapy noted here is close to the original, hoped-for vision for the field, in which transplanted cells survive and integrate with patient tissue in order to carry out useful work, restoring lost cells and tissue structure to improve function. That, as it turned out, is very hard to achieve. Typically, transplanted cells near all die, and the benefits produced by presently available stem cell therapies, such as reduced chronic inflammation, are instead mediated by signals secreted by the stem cells in the short time that they survive. Nonetheless, cell therapies in which large fractions of the transplanted cells survive to restore function remain an important goal in the field, and results such as those reported here help to keep that original vision alive.

In mice whose sense of smell has been disabled, a squirt of stem cells into the nose can restore olfaction, researchers report. The introduced globose basal cells, which are precursors to smell-sensing neurons, engrafted in the nose, matured into nerve cells, and sent axons to the mice's olfactory bulbs in the brain. "We were a bit surprised to find that cells could engraft fairly robustly with a simple nose drop delivery. To be potentially useful in humans, the main hurdle would be to identify a source of cells capable of engrafting, differentiating into olfactory neurons, and properly connecting to the olfactory bulbs of the brain. Further, one would need to define what clinical situations might be appropriate, rather than the animal model of acute olfactory injury."

Researchers have tried stem cell therapies to restore olfaction in animals previously, but it's been difficult to determine whether the regained function came from the transplant or from endogenous repair stimulated by the experimental injury to induce a loss of olfaction. So the team developed a mouse whose resident globose basal cells only made nonfunctional neurons, and any restoration of smell would be attributed to the introduced cells.

The team developed the stem cell transplant by engineering mice that produce easily traceable green fluorescent cells. The researchers then harvested glowing green globose basal cells (as identified by the presence of a receptor called c-kit) and delivered them into the noses of the genetically engineered, smell-impaired mice. Four weeks later, the team observed the green cells in the nasal epithelium, with axons working their way into the olfactory bulb. Behaviorally, the mice appeared to have a functioning sense of smell after the stem cell treatment. Unlike untreated animals, they avoided an area of an enclosure that had a bad smell to normal mice.

Enzymes of Xenobiotic Metabolism and Variation in Human Longevity

How much might varying competence in managing foreign compounds and biological substances, xenobiotics such as those resulting from infection or environmental toxins, determine the observed variations in human longevity? Researchers here look for variations in the genes encoding for xenobiotic metabolizing enzymes involved in dealing with these invading substances, and find a modest association with longevity in humans. While interesting, it is worth remembering that this sort of genetic study tends to fail in replication. It is rare for any association between genetic variants and longevity to reliably show up in more than one study population.

Aging is a complex phenotype responding to a plethora of drivers in which genetic, behavioral, and environmental factors interact with each other. This can be conceptualized in terms of exposome - that is, the totality of exposures to which an individual is subjected throughout a lifetime and how those exposures affect health. The exposome basically includes a wide variety of toxic or potentially harmful compounds of exogenous (environmental pollutants, dietary compounds, drugs) or endogenous (metabolic by-products such as those resulting from inflammation or lipid peroxidation, oxidative stress, infections, gut flora) origin and related biological responses during the life course.

The individual ability to properly cope with xenobiotic stress can influence susceptibility to diseases and, thus, the quality and the rate of aging, phenotypes that certainly result from the cumulative experiences over lifespan. Additionally, in all the different theories proposed to explain the aging process, a common denominator remains the progressive decline of the capacity to deal with environmental stressors to which the human body is constantly exposed.

In this scenario, a crucial role can be played by the coordinated activity of cellular mechanisms evolved for reducing the toxicity of endogenous and xenobiotic compounds to which humans are exposed. These mechanisms comprehend a broad range of reactions of detoxification that make harmful compounds less toxic, more hydrophilic, and easier to be excreted. The main effectors of these mechanisms are a large number of enzymes and transporters, collectively referred to as xenobiotic-metabolizing enzymes (XMEs) or drug metabolizing enzymes (DMEs).

With aging, there is a decline in the ability to mount a robust response to xenobiotic insults. This is somewhat attributed to the age-related reduction in liver mass, which can result in reduced metabolism rates and in the decreased kidney and liver blood flows, which can result in reduced excretion and elimination of xenobiotic and its metabolites. In addition, a reduction in the activity of XMEs and DMEs and the consequent fall in biotransformation capacity have been reported in both old animals and humans.

We reasoned that genetic variants of XME genes might affect the chance to live a long life. In order to test this hypothesis, we screened a set of 35 SNPs in 23 XME genes and their association with aging and survival in a cohort of 1112 individuals aged 20-108 years. Four variants in different genes differently impacted the longevity phenotype. In particular, the highest impact was observed in the age group 65-89 years, known to have the highest incidence of age-related diseases. In fact, genetic variability of these genes we found to account for 7.7% of the chance to survive beyond the age of 89 years. Results presented herein confirm that XME genes, by mediating the dynamic and the complex gene-environment interactions, can affect the possibility to reach advanced ages, pointing to them as novel genes for future studies on genetic determinants for age-related traits.

Impaired Mitophagy and Mitochondrial Function in Alzheimer's Disease

Alzheimer's disease starts with an accumulation of amyloid-β, which disrupts cellular metabolism sufficiently to lay the grounds for the chronic inflammation and aggregation of tau protein that characterize the later, severe stage of the condition. Here, researchers make the argument that a fair degree of this progression is mediated via dysfunction of mitochondria and the quality control mechanisms of mitophagy, normally responsible for removing damaged mitochondria, and that this dysfunction is caused by amyloid-β.

Mitochondria are the power plants of the cell, and a faltering of their activity has profoundly disruptive effects. Needless to say, mitochondrial dysfunction is a characteristic feature of aging. This leads to the point that aging is a complex enough phenomenon for it to be possible to argue that mitochondrial dysfunction contributes to amyloid-β and tau aggregation, not vice versa. Or that both directions of causation are real phenomena. These are not simple, easily modeled systems. The fastest way to a definitive answer is likely that of building rejuvenation therapies capable of restoring mitochondrial function to youthful levels, and observing the result.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta (Aβ) formation and accumulation, hyperphosphorylated tau (P-Tau) formation and accumulation, deregulated microRNAs, synaptic damage, and neuronal loss in patients with AD. Among these, mitochondrial dysfunction and synaptic damage are early events in the disease process.

Recent research also revealed that Aβ and P-Tau-induced defective autophagy and mitophagy are prominent events in AD pathogenesis. Age-dependent increased levels of Aβ and P-Tau reduced levels of several autophagy and mitophagy proteins. In addition, abnormal interactions between (1) Aβ and mitochondrial fission protein Drp1; (2) P-Tau and Drp1; and (3) Aβ and PINK1/parkin lead to an inability to clear damaged mitochondria and other cellular debris from neurons. These events occur selectively in affected AD neurons.

In terms of rescuing and enhancing autophagy and mitophagy, reduced Drp1 and Aβ and P-tau levels and enhancing the levels of PINK1/parkin are proposed to rescue and/or maintain mitophagy and autophagy in affected AD neurons. The continuous clearance of cellular and mitochondrial debris is important for normal cellular function. We need more research on autophagy and mitophagy mechanisms and therapeutic aspects using cell cultures, animal models, and human AD clinical trials.

MiR-135a-5p as a Target to Induce Greater Neurogenesis

Neurogenesis is the creation of new neurons in the brain, followed by their integration into neural circuits. It is generally agreed upon in the research community that increasing the degree of neurogenesis that takes place in the aging brain is a desirable therapeutic goal, particularly since this process appears to decline with age. Greater neurogenesis should increase both resilience to injury and cognitive function. A great deal of work takes place in this part of the field, though it is a complicated business and is not progressing towards practical therapies anywhere near as rapidly as desired. The research here is a representative example of the sort of work that has taken place over the past decade: numerous regulatory molecules have been identified, and proposed as a basis for intervention. Whether anything comes of this one remains to be seen.

In most mammalian species, the postnatal subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) maintains a population of neural precursor cells (NPCs) retaining the lifelong capability to generate new neurons and astrocytes. However, this process inexorably declines with age, and this decline has been correlated with the loss of cognitive abilities and the occurrence of several brain pathologies. Currently, many translational concepts for preserving cognitive abilities in the aging brain thus aim at sustaining, or even increasing, the potential for cognitive plasticity and flexibility that is contributed by the adult-generated neurons.

Environmental enrichment and physical activity (e.g., voluntary running in a wheel) potentiate adult neurogenesis in rodents. The positive response of adult neurogenesis to these stimuli is maintained into old age and counteracts the age-associated cognitive decline in rodents and likely in humans. However, the cellular and molecular mechanisms underlying homeostasis of adult neurogenesis and its response to environmental stimuli remain elusive. We hypothesize that exploiting these mechanisms is relevant for preventing age-related cognitive decline in humans and that our animal models can contribute to providing evidence-based recommendations for an active lifestyle for successful aging.

MicroRNAs (miRNAs) are small noncoding RNAs which, by post-transcriptional repression of hundreds of target messenger RNAs (mRNAs) in parallel, tune the entire cell proteome. The functional synergism of few miRNAs achieves gene regulation essential for proliferation, cell fate determination, and survival. Interestingly, running stimulates hippocampal NPC proliferation and alters miRNA expression in rodents. Hence, we hypothesize that investigating miRNAs involved in running-induced neurogenesis would allow the identification of the most prominent pathways that constrain NPC proliferative potential in the adult mouse hippocampus.

Here, we show that exercise increases proliferation of neural precursor cells (NPCs) of the mouse dentate gyrus (DG) via downregulation of microRNA 135a-5p (miR-135a). MiR-135a inhibition stimulates NPC proliferation leading to increased neurogenesis, but not astrogliogenesis, in DG of resting mice, and intriguingly it re-activates NPC proliferation in aged mice. We identify 17 proteins (11 putative targets) modulated by miR-135 in NPCs. MiR-135 is the first noncoding RNA essential modulator of the brain's response to physical exercise. Prospectively, it might represent a novel target of therapeutic intervention to prevent pathological brain aging.

Exosomes in Harmful Senescent Cell Signaling

Extracellular vesicles such as exosomes are an important component of cell signaling, small membrane-bound packages of molecules that are passed around in large numbers by cell populations. The presence of lingering senescent cells is one of the root causes of aging. These errant cells never make up more than a small fraction of the overall cell population, even in very late life, but they cause considerable disruption and harm through the inflammatory signaling that they generate. Extracellular vesicles are here, as elsewhere, an important part of that signaling process.

Given that the most straightforward path towards therapy is the destruction of senescent cells, there probably isn't all that much that can be accomplished therapeutically more rapidly and effectively via a focus on exosomes. As authors of this open access paper point out, however, it is still a potentially useful area of research from the point of view of expanding knowledge of the fundamental biology of aging, how aging progresses in detail. Given that senescent cells accelerate dysfunction, and given that they do this via signaling, mapping that signaling in greater detail will probably teach us something.

Communication between cells is quintessential for biological function and cellular homeostasis. Membrane-bound extracellular vesicles known as exosomes play pivotal roles in mediating intercellular communication in tumor microenvironments. These vesicles and exosomes carry and transfer biomolecules such as proteins, lipids, and nucleic acids. Here we focus on exosomes secreted from senescent cells.

Cellular senescence can alter the microenvironment and influence neighbouring cells via the senescence-associated secretory phenotype (SASP), which consists of factors such as cytokines, chemokines, matrix proteases, and growth factors. This review focuses on exosomes as emerging SASP components that can confer pro-tumorigenic effects in pre-malignant recipient cells. This is in addition to their role in carrying SASP factors. Transfer of such exosomal components may potentially lead to cell proliferation, inflammation, and chromosomal instability, and consequently cancer initiation.

Senescent cells are known to gather in various tissues with age; eliminating senescent cells or blocking the detrimental effects of the SASP has been shown to alleviate multiple age-related phenotypes. Hence, we speculate that a better understanding of the role of exosomes released from senescent cells in the context of cancer biology may have implications for elucidating mechanisms by which aging promotes cancer and other age-related diseases, and how therapeutic resistance is exacerbated with age.

Towards Targeting the Toxins of Oral Bacteria in the Alzheimer's Brain

There is a clear association between poor dental hygiene and incidence of Alzheimer's disease, but is this a direct mechanism, or more a reflection of other health practices and lifestyle choices made by the sort of person who has poor dental hygiene? The direct mechanisms are thought to be (a) chronic inflammation, in the sense that gum disease allows bacteria and bacterial toxins access to the bloodstream, and this will rouse the immune system or (b) some other effect arising from the impact of bacterial toxins on critical cells in the brain.

That these direct mechanisms exist is clear: the evidence here adds to numerous past studies that show the gingipains secreted by Porphyromonas gingivalis, the most important bacterial species in gum disease, can be a real problem. But what is the size of the effect in practice, in humans rather than in animal models set up specifically to demonstrate the mechanisms in question? Recent epidemiological work suggests it is only a small contribution to the risk of dementia such as Alzheimer's disease. The best way forward is probably exactly that demonstrated here, which is to say find a way to fix the problem, then test that fix and observe the results.

Alzheimer's disease (AD) patients exhibit neuroinflammation consistent with infection. Infectious agents have been found in the brain and postulated to be involved with AD, but robust evidence of causation has not been established. The recent characterization of amyloid-β (Aβ) as an antimicrobial peptide has renewed interest in identifying a possible infectious cause of AD. Chronic periodontitis (CP) and infection with Porphyromonas gingivalis - a keystone pathogen in the development of CP - have been identified as significant risk factors for developing Aβ plaques, dementia, and AD.

A prospective observational study of AD patients with active CP reported a notable decline in cognition over a 6-month period compared to AD patients without active CP, raising questions about possible mechanisms underlying these findings. P. gingivalis lipopolysaccharide has been detected in human AD brains, promoting the hypothesis that P. gingivalis infection of the brain plays a role in AD pathogenesis.

P. gingivalis is an asaccharolytic Gram-negative anaerobic bacterium that produces major virulence factors known as gingipains. We hypothesized that P. gingivalis infection acts in AD pathogenesis through the secretion of gingipains to promote neuronal damage. We found that gingipain immunoreactivity in AD brains was significantly greater than in brains of non-AD control individuals. In addition, we identified P. gingivalis DNA in AD brains and the cerebrospinal fluid (CSF) of living subjects diagnosed with probable AD, suggesting that CSF P. gingivalis DNA may serve as a differential diagnostic marker. We developed and tested potent, selective, brain-penetrant, small-molecule gingipain inhibitors in vivo. Our results indicate that small-molecule inhibition of gingipains has the potential to be disease modifying in AD.

Targeting GATA Transcription Factor to Upregulate Autophagy

Many approaches exist to boost the operation of the cellular housekeeping processes of autophagy in order to modestly slow the progression of aging. The improved health and longevity derived from the practice of calorie restriction largely occurs due to increased autophagy, for example. Disable autophagy, and studies have shown that the robust and reliable increase in life span in calorie restricted animals no longer occurs.

Cellular processes such as autophagy are regulated by a complex network of proteins, giving many possible points of intervention. Equally, it is a challenge to decipher such systems in order to find points of intervention that are not more trouble than they are worth. Present interventions to enhance autophagy that are making their way towards the clinic are calorie restriction mimetics, discovered compounds that recreate a little of a known good form of intervention. So far there has been little clinical progress in deliberate, targeted approaches to upregulating autophagy independently of the mechanisms of calorie restriction. Still, potential new targets in the regulation of autophagy, such as the example here, continue to appear year after year as research progresses.

A person born today will likely spend the last decade of her or his life suffering from age-associated conditions, like neurodegeneration, cardiovascular disease, diabetes, or cancer. Anti-aging strategies aim at closing this gap between life- and healthspan, either by behavioral - mostly dietary - interventions or by pharmacologically targeting cellular pathways that influence aging. Thus far, dozens of anti-aging compounds have been described, and most of them act via decreased nutrient signaling and/or reduced protein acetylation, which seems to be a common hallmark among pharmacological anti-aging interventions. Nevertheless, novel molecules, especially those acting via alternative pathways, are needed, since they might be used in new combinatory approaches.

In a recent study, we investigated different classes of flavonoids, a group of secondary metabolites from plants, for their ability to promote longevity. For that purpose, we conducted a high-throughput screen based on chronological aging of the yeast Saccharomyces cerevisiae, an established model for the aging of post-mitotic cells. The compound that most consistently improved the screened parameters was the chalcone 4,4'-dimethoxychalcone (DMC). Subsequent experiments unraveled that DMC administration prolonged lifespan in nematodes and fruit flies and decelerated cellular senescence in human cancer cells.

Many anti-aging compounds induce autophagy, an intracellular mechanism that recycles superfluous or damaged cellular material. DMC treatment led to elevated autophagy levels in all organisms tested, including yeast, nematodes, flies, mice and cultured human cells. Moreover - unlike many other anti-aging compounds - DMC treatment did not reduce mTOR signaling, and in yeast, the anti-aging effects depended neither on the mTOR component Tor1, nor on the sirtuin-1 homolog Sir2. Instead, a mechanistic screen in yeast revealed that DMC required the depletion of the GATA transcription factor (TF) Gln3 to exert its anti-aging effects.

GATA transcription factors (TFs) constitute a conserved family of zinc-finger TFs that fulfill diverse functions across eukaryotes. Accumulating evidence suggests that GATA TFs also play a role in lifespan regulation. This data places GATA TFs in the limelight as actionable targets for postponing age-associated disease.

Deterioration of Immune Responses in the Aged Gut in Mice is Reversed via Transplantation of Youthful Gut Microbes

Changes in the gut microbiome over the course of aging occur in parallel to a decline in immune function. The direction of causation is unclear, as both systems influence one another. Indeed, causation can exist in both directions simultaneously, as there are a great many distinct mechanisms involved in the interactions between gut microbes and the host immune system. The balance of evidence at the moment favors gut microbes as the cause and immune issues as the consequence. The results here add to those of other studies that suggest it is shifts in the gut microbe populations that drive significant dysfunction in the immune system, and that these shifts can be reversed (at least temporarily) via comparatively simple, brute-force strategies.

One of the organs that is significantly affected by age is the gastrointestinal tract and the gut-associated microbiome. These commensal microorganisms are essential for health, affecting the functions of multiple bodily systems, such as host metabolism, brain functions, and the immune response. Older individuals have age-related alterations in gut microbial composition, which have been associated with increased frailty, reduced cognitive performance, immune inflammaging and an increased susceptibility to intestinal disorders.

What drives these age-associated changes in the gut microbiota remains unknown. The microbiome is shaped by many factors including host genetics, early life events, diet, and the gut immune system. While some of these factors remain relatively constant throughout life, the function of the immune system is known to deteriorate with age. This prompts the hypothesis that dysbiosis of the intestinal microbiome in older individuals may be driven by altered cross-talk between the host immune system and the microbiota. The gut immune system can regulate the composition of the microbiome by the production of immunoglobulin A (IgA) antibodies that coat commensal bacteria. In the gastrointestinal tract, IgA antibodies are either produced by short-lived plasma cells in the lamina propria or from plasma cells that arise from germinal centre (GC) reactions in Peyer's patches (PPs).

Studies indicate clearly that the microbiome is causally influenced by the GC reaction. In the case of the gut-associated defects seen with advancing age in the GC reaction and gut microbiota, however, the direction of causation is unclear. Here, we report that the defective GC reaction in aged mice could be boosted by direct faecal transplantation from adult donors and by oral administration of cholera toxin. This demonstrates that the age-dependent defect in the gut GC reaction is not irreversible, but can be corrected by changing the microbiota or by delivery of a bacterial derived toxin.


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