Senolytic Therapies to Clear Senescent Cells Should Benefit Cancer Patients

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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.

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

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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.


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Exosomes in Harmful Senescent Cell Signaling

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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.


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Impaired Mitophagy and Mitochondrial Function in Alzheimer's Disease

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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.


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Progress Towards Blocking Alternative Lengthening of Telomeres in Cancer

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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.

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

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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.


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

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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.

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Supplementing with Taurine: A Vital Amino Acid

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Supplementing with Taurine: A Vital Amino Acid
Nadia Anderson, M.P.H.

A high dietary intake of the amino acid taurine, sometimes considered one of the best kept secrets of optimal health, has been identified as a potentially key longevity factor shared amongst the world’s longest-living populations.1 Although taurine has often been overlooked, researchers have concluded that due to “its functional significance in cell development, nutrition, and survival, taurine is undoubtedly one of the most essential substances in the body.”2 Taurine is the most abundant amino acid in human cells, but the body produces it in insufficient quantities.3,4 Taurine’s wide range of important functions in the human body have led one of the world’s leading nutritional longevity experts to call it a “longevity nutrient.”3

What are the benefits of taurine?

Taurine is involved in almost every aspect of health. It supports cardiovascular health, insulin sensitivity, mitochondrial function, neurologic health and even athletic performance and recovery. Talk about comprehensiveness!

Related Article: Taurine Protects Against Age-Related Brain Changes

Who needs to supplement with taurine?

Taurine is predominantly found in animal-derived foods such as dairy, meats, fish and shellfish, and is virtually absent from many plant foods such as legumes (including soy), nuts, and vegetables.5,6 Those consuming a plant-based or vegan diet with little to no animal-derived foods would benefit from supplementing with taurine. Clinical studies using taurine at doses of 1,000-6,000 mg have reported beneficial effects.7,8 While those with a vegan or vegetarian diet may be at greatest risk of low taurine levels, taurine is necessary for so many vital bodily functions that nearly anyone can benefit from supplementing with taurine.

The safety of supplemental taurine

Is taurine derived from bull urine? No. It is a misconception that the amino acid is derived from bull urine or semen. Taurine is a common addition to many energy drinks, such as Red Bull. Although energy drinks can provide between 600-1,000 mg of taurine, regular consumption is not suggested. Unlike excessive energy drink consumption, taurine supplementation has a strong record of safety.9


  1. Yamori Y, Liu L, Mori M, et al. Taurine as the nutritional factor for the longevity of the Japanese revealed by a world-wide epidemiological survey. Adv Exp Med Biol. 2009;643:13-25.
  2. Ripps H, Shen W. Review: Taurine: A “very essential” amino acid. Mol Vis. 2012;18:2673-86.
  3. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):10836-10844. doi: 10.1073/pnas.1809045115.
  4. Lourenço R1, Camilo ME. Taurine: a conditionally essential amino acid in humans? An overview in health and disease. Nutr Hosp. 2002 Nov-Dec;17(6):262-70.
  5. Wójcik O, Koenig K, Zeleniuch-Jacquotte A, Costa M, Chen Y. The potential protective effects of taurine on coronary heart disease. Atherosclerosis. 2010 Jan; 208(1): 19.
  6. U.S.D.A., Agricultural Marketing Service. Taurine Handling/Processing. Accessed 05/29/2019.
  7. Waldron M, Patterson SD, Tallent J, Jeffries O. The Effects of an Oral Taurine Dose and Supplementation Period on Endurance Exercise Performance in Humans: A Meta-Analysis. Sports Med. 2018 May;48(5):1247-1253.
  8. Waldron M, Patterson SD, Tallent J, Jeffries O. The Effects of Oral Taurine on Resting Blood Pressure in Humans: a Meta-Analysis. Curr Hypertens Rep. 2018 Jul 13;20(9):81.
  9. Schaffer S, Kim HW. Effects and Mechanisms of Taurine as a Therapeutic Agent. Biomol Ther (Seoul). 2018 May; 26(3): 225–241.

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Enzymes of Xenobiotic Metabolism and Variation in Human Longevity

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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.


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

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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.


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