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

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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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Targeting GATA Transcription Factor to Upregulate Autophagy

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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.


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CoQ10’s Potential Capabilities for Your Health

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Hundreds of thousands Americans are struggling with heart disease,1 a condition that not only takes its toll on a person’s health, but on the wallet too. For example, statin drugs, which are prescribed to lower cholesterol in the belief the drugs will help prevent heart attacks, are top sellers for drug companies. At their peaks before losing their patents, Crestor made $6.6 billion a year at its peak; Lipitor $14 billion in one year; and Pravachol and Zocor $4 billion and $3 billion, respectively.2

And now that a new injectable drug to lower cholesterol that costs $14,000 per patient per year is on the market, it’s expected that cholesterol-lowering drugs alone will make Americans’ health care costs “unsustainable.”3

At least 1 in 4 Americans over 40 years old is taking statins to lower their risk for cardiovascular conditions and stroke.4 However, statins have been linked to serious side effects, including liver and muscle damage.5 These are important issues that you may want to discuss with your doctor if you’re prescribed statins.

There is something else you might want to discuss as well — if your doctor doesn’t mention it — and that would be to add a daily CoQ10 supplement to your health regimen. But what is CoQ10, and how can it benefit your health and heart?

What Is CoQ10?

CoQ10, short for coenzyme Q10, is an antioxidant naturally produced by the body6 and found in your mitochondria.7 There are two forms of CoQ10: ubiquinone8 and ubiquinol, CoQ10’s reduced form that’s considered a far more effective alternative because it’s eight times better absorbed.9 CoQ10 is crucial for the production of adenosine triphosphate (ATP), which aids in providing energy for your body’s cells.10

In his book, “The Sinatra Solution: Metabolic Cardiology,” cardiologist Dr. Stephen Sinatra notes that your body, because of reductase enzymes, can convert CoQ10 into ubiquinol from the foods and supplements you eat and take.11

However, as you age your body produces less CoQ10.12 At this point, CoQ10 supplements may be vital to help optimize your body’s levels and alleviate certain conditions. You can find CoQ10 in capsule, tablet and IV forms.13 It’s also used as an ingredient in skincare products.14,15

Food Sources of CoQ10

There are foods with CoQ10 you can eat to help increase your body’s levels of it. Notable examples of CoQ10-rich foods include:16

There has been research highlighting the positive impact of eating chlorophyll-rich vegetables exposed to sunlight, since they help promote CoQ10 production.19 You can increase your chlorophyll intake by eating these vegetables, ideally organic:20,21,22

  • Cucumber
  • Green beans
  • Green peas
  • Kale23
  • Mustard greens
  • Swiss chard24
  • Parsley

High-quality pistachio nuts25 and organic kiwi fruits26 may be considered too. Just make sure to consume kiwi in moderation since they contain fructose, which can upset your mitochondria when consumed in high quantities.

Notable Health Benefits of CoQ10

CoQ10 provides positive impacts to cardiovascular health. For instance, elderly Swedish subjects between 70 and 88 years old who took CoQ10 supplements together with selenium reported improved heart function and significantly decreased risk for death due to cardiovascular causes.27

In other studies, CoQ10 was also able to help decrease effects of oxidative stress-triggered mitochondrial dysfunction,28 minimize mitochondrial damage29 and promote production of new mitochondria, particularly in the brain.30 Findings show that CoQ10 also delivers the following health-boosting properties:

Anti-inflammatory — Ubiquinol may have effects on two markers linked to cardiovascular diseases: N-terminal pro-brain natriuretic peptide (NT-proBNP) and gamma-glutamyl transferase (GGT).

In a 2015 study, elderly subjects with higher ubiquinol serum levels had reduced quantities of NT-proBNP, helping reduce their risk of heart failure.31 Meanwhile, authors of a 2014 article noted that ubiquinol supplements assisted in reducing serum GGT activity and effects of oxidative stress in humans.32

Antioxidant CoQ10 can help combat free radicals and lessen their damage33 as it’s a fat-soluble antioxidant found in your cell membranes and mitochondria.34

There’s also research suggesting that CoQ10 aids in enhancing the health of your:

Heart — The book “High Blood Pressure: Arrest This Silent Killer Before It Strikes and You Will Add Years to Your Life” says that CoQ10 may aid in increasing your heart’s ability to pump more powerfully, possibly enabling circulation and better blood flow throughout your body. However, the mechanism responsible for this isn’t fully understood.35

Skin — Your CoQ10 levels decrease as you get older,36 and reduce your body’s ability to produce collagen and elastin.37 These two skin proteins are responsible for boosting your skin’s strength and elasticity (collagen),38 and pliability and resilience (elastin).39,40 If your body contains insufficient amounts of these proteins, wrinkles and saggy skin may appear.41,42

CoQ10 may also have an ability to combat free radicals responsible for cell damage. CoQ10 is able to penetrate into your skin and deliver antioxidant effects that may aid with regulating your cells’ energy levels.43

What Does CoQ10 Do?

CoQ10 is good for the body’s cells, as it’s essential for producing the energy they need.44 Supplements containing this antioxidant not only will help address a CoQ10 deficiency, but also may help with:

  • Migraines45
  • Diabetes46,47
  • Fatigue caused by fibromyalgia48
  • Arrhythmia49
  • Heart failure50
  • Mitral valve prolapse (ideally in combination with magnesium)51
  • Heart transplant candidates52
  • Age-related macular degeneration
  • Diabetic neuropathy
  • Muscular dystrophy53

Multiple studies have revealed that CoQ10 has potential in reducing high blood pressure levels.54,55,56 People with blood pressure-related problems may find CoQ10 supplements useful, as lower levels were noticeable among those with high blood pressure.57

CoQ10 supplements may be linked to fertility effects too. The presence of CoQ10 in semen may result in improved antioxidant abilities and yield positive impacts toward sperm concentration, morphology and motility.58 An animal study done on aged subjects also showed that CoQ10 supplements assisted in promoting ovulation, inhibiting loss of ovarian reserves and boosting mitochondrial function.59

Studies Conducted on CoQ10

Interest surrounding CoQ10 after its discovery in 195760 grew and paved the way for researchers to conduct studies with it. In fact, British biochemist Peter Mitchell, Ph.D., was awarded the 1978 Nobel Prize in biochemistry because he was able to thoroughly describe cellular power production, which involved CoQ10.61 Other studies also found that CoQ10 may assist with:

Addressing migraines — Nutritional deficiencies, particularly of CoQ10, vitamin D, alpha-lipoic acid, magnesium and many more, may play a role in the onset of migraines.62 This is an important breakthrough, as migraines affect at least 1 in 7 Americans yearly63 and is considered by the WHO as the “sixth highest cause worldwide of years lost due to disability.”64

In 2015, a randomized, placebo-controlled and double-blind trial revealed that a commercial formula containing CoQ10, riboflavin (vitamin B2) and magnesium, was able to reduce migraine frequency and lessened its intensity, compared to a placebo.65

A 2016 study conducted by Dr. Suzanne Hagler and colleagues at the Cincinnati Children’s Headache Center highlighted that children, teenagers and young adults who often dealt with migraines had mild deficiencies of CoQ10 and vitamins B2 (riboflavin) and D. Girls and young women were more CoQ10-deficient, while boys and young men were more vitamin-D deficient.66 However, more research is needed to fully confirm this link.67

Combating cardiovascular issues — The Q-Symbio study, which was conducted in 2014, involved 420 people who were randomly chosen to take either a 100-milligram dose of CoQ10 three times a day or a placebo, and underwent therapy during the course of the study. Results indicated that CoQ10 supplements played a role in:68

Lessening cardiovascular mortality (9% for the CoQ10 group versus 16% for the placebo group) and all-cause mortality (10% for the CoQ10 group versus 18% for the placebo group)

Reducing hospital stays due to heart failure

Alleviating mitochondrial disorders and neurodegenerative diseases — A 2004 animal study showed that CoQ10 was able to raise brain concentrations among mature and older animals. This effect may be linked to CoQ10’s potential in helping alleviate mitochondrial disorders and neurodegenerative diseases like Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).69

Predicting dementia risk — Authors of a 2014 study revealed that CoQ10 levels may serve as a predictor for the onset of dementia.70

Boosting exercise performance — Subjects in this 2008 study who took CoQ10 supplements had higher amounts of it in their muscles, experienced less oxidative stress during and after exercise and reported increased exercise endurance.71

How Should You Take CoQ10?

Because it’s a fat-soluble nutrient, CoQ10 supplements are best taken with a fatty meal or a small amount of healthy fat like coconut oil, olive oil or MCT oil. Before taking CoQ10, though, talk to your physician to help determine the ideal dose needed for your condition. CoQ10 levels may be checked via multiple types of tests.72  

Side Effects of CoQ10

Generally, CoQ10 supplements are deemed safe, although they can cause diarrhea, nausea, heartburn,73 headaches, rashes, fatigue and dizziness.74 However, unless they’re given under the supervision of a health care provider or physician, CoQ10 supplements should be avoided by people younger than 18 years old.75

The same principle applies if you’re pregnant or breastfeeding, since studies are lacking regarding CoQ10’s effectivity and safety for both groups.76 CoQ10 supplements may interact with the following drugs too:77

  • Chemotherapy drugs like daunorubicin (Cerubidin) and doxorubicin (Adriamycin) — If you’re undergoing chemotherapy, talk to your oncologist before taking antioxidants or supplements.
  • Blood pressure medications like diltiazem (Cardizem), metoprolol (Lopressor or Toprol), enalapril (Vasotec) and nitroglycerin (Nitrostat or Nitrobid) — CoQ10 supplements are said to boost the effectiveness of these medications, but more research is needed to support these findings.
  • Timolol drops (Betoptic) for glaucoma — Taking CoQ10 may reduce its heart-related side effects without inhibiting its effectivity.
  • Anticoagulants like warfarin (Coumadin) — These drugs’ effects may be reduced if you take CoQ10 supplements alongside them, and may raise your blood clot risk.78

PennState’s Milton S. Hershey Medical Center adds that taking the following medicines can lower your body’s CoQ10 levels:79

  • Statins for cholesterol like atorvastatin (Lipitor), lovastatin (Mevacor), pravastatin (Pravachol) and simvastatin (Zocor)
  • Fibric acid derivatives for cholesterol like gemfibrozil (Lopid)
  • Beta-blockers for high blood pressure like atenolol (Tenormin), labetolol (Normodyne), metoprolol (Lopressor or Toprol) and propranolol (Inderal)
  • Tricyclic antidepressants like amitriptyline (Elavil), doxepin (Sinequan) and imipramine (Tofranil)

CoQ10: This Antioxidant May Be More Important Than You Realize

Optimizing your body’s CoQ10 levels can be a good decision, especially if you’re keen on improving your overall health and enhancing your body function. Most research surrounding this antioxidant is positive, providing substantial evidence that highlights its importance.

Despite its numerous uses and benefits, remember that CoQ10 supplements aren’t a magic pill that’ll immediately heal your ailments. While raising your body’s levels of this nutrient is important, maintaining a healthy lifestyle that focuses on eating nutritious food and exercising on a frequent basis should still be your main priorities.

Frequently Asked Questions About CoQ10

Q: What is CoQ10 made from?

A: CoQ10 is a substance similar to a vitamin that’s naturally produced by the body,80 and is found in the mitochondria.81  

Q: What does ubiquinol do for your body?

A: Ubiquinol is the reduced form of CoQ10.82 While information about its benefits may be lacking because most studies are focused on the full form of CoQ10, initial research has stated that it may help:

  • Lower blood pressure levels
  • Reduce exercise-induced muscle damage83
  • Inhibit adverse effects that may be triggered by free radicals and oxidative stress84

Q: Is CoQ10 safe?

A: A safety assessment published in 2008, which was based on data from both preclinical and clinical studies, revealed that CoQ10 is safe to use as a dietary supplement.85 However, it’s said to cause diarrhea, nausea or heartburn in some people,86 as well as interact with other medicines.87 If you’re interested in CoQ10 supplements, consult your physician to learn if it’s safe for you and what the ideal dose for your condition is.

Q: Is CoQ10 good for lowering cholesterol?

A: CoQ10 may be useful if you have high blood pressure88 or cholesterol levels, because your body’s stores of this antioxidant may be low at this point.89

Not much evidence has shown if CoQ10 supplements are ideal for lowering cholesterol levels. However, there’s initial research showing CoQ10 supplements may decrease side effects caused by statins that lower cholesterol levels.90

Q: Should I take CoQ10?

A: If you’re not sure if you need to increase your body’s CoQ10 levels or not, talk to your doctor. Some tests may be suggested to check your body’s levels of this antioxidant.91 People under 18 years old and pregnant or breastfeeding women should not take CoQ10 supplements.92,93

Q: How much CoQ10 should you take if you are on statins?

A: If you plan on taking statins at the same time as CoQ10 supplements, consult your doctor to determine the right dosage for your condition.

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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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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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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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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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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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