Understanding Your Liver Health

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Your liver weighs about 3 pounds and is located on the right side of your abdomen. Reddish brown in color, it’s rubbery to the touch and protected by your rib cage.1 Your liver is the largest solid organ and one of the largest glands in your body, carrying out over 500 essential tasks to maintain optimal health.2

One of the main jobs of the organ is to process and purify blood coming from the hepatic artery and the hepatic portal vein. The liver has two main lobes, each of which have eight segments.3 Each segment is made up of approximately 1,000 lobules connected by small ducts that eventually come together to form the common hepatic duct.4

In addition to filtering your blood, the liver regulates many chemical levels and excretes bile your intestines use to help break down fat.5 Your liver also produces cholesterol, stores and releases glucose as needed, and regulates blood clotting. As your liver metabolizes chemicals or breaks down harmful substances, they are released into the bile or blood.

Bile enters your intestines and ultimately leaves your body in stool, while blood by-products are filtered out by your kidneys and leave through your urine. Your body stores vitamins A, D, E, K and B12 in the liver,6 and the liver functions as part of the phagocyte system, a portion of the immunological function of your body.7

In other words, your liver is highly important to your health. It is also the only organ in your body able to regenerate.8 In mice, if two-thirds of the liver is removed, the tissue regrows to its normal size within seven days. In humans, as long as 25 percent of healthy tissue remains, it regrows without any loss of function in approximately 15 days.

What Do Your Liver Enzymes Tell You?

Although most health practitioners rely on reference ranges provided by a laboratory or defined by their hospital facility, there is an evidence-based set of optimal ranges that more readily predict underlying pathology. Dr. Brian Walsh is a naturopathic physician who has extensive training in molecular biological pathways.

In an interview posted in my previous article, “What Basic Blood Tests Can Tell You About Your Health,” one topic we discussed were two of the tests commonly used to evaluate liver function — the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The laboratory value ranges for the high end for AST is 40 units per liter (U/L) and 56 U/L for ALT.9

However, Walsh believes the medical literature10 “very clearly show that, a) men and women should have different AST and ALT reference ranges, and b) [the ideal range] is not much above 20 U/L.”

These two specific enzymes are found mainly in your liver. They are elevated when there is a form of liver damage or injury. A sudden acute jump may indicate injury to the liver, while chronically elevated levels may suggest ongoing damage.

Some of the more common diseases triggering elevated ALT and AST are viral hepatitis A, B or C, cirrhosis of the liver, alcoholic fatty liver disease, hemochromatosis (iron overload) or diminished blood flow from shock or heart failure.11

Another measurement important in the prediction of mortality is gamma-glutamyl transferase (GGT). This liver enzyme is correlated with iron toxicity, increased disease risk and all-cause mortality.12 In an interview with Gerry Koenig, chairman of the board at the Iron Disorders Institute,13 we discuss the importance of GGT and its involvement in glutathione metabolism and transport of amino acids.

GGT is an important measurement of liver damage, potentially greater than AST or ALT, and may also be used as a biomarker for excess iron and early death. Determining mortality risk is a chief responsibility of insurance underwriters who use laboratory values and biomarkers to assign risk scores.

Liver function tests, particularly GGT, have become a central factor in the life insurance underwriting process.14 GGT is necessary in the production of your body’s primary antioxidant, glutathione. When elevated, it breaks glutathione down.15

Researchers have also found variations in enzyme levels are inheritable and may change by age and sex. To examine the genetic architecture, researchers sampled twins, their siblings, parents and spouses, and found the same genes influence liver enzymes, but the relative contribution to the variation differs in males and females.16

The Importance of Monitoring Your Iron Levels for Liver Health

Another factor associated with liver damage is iron overload. Iron is one of the most common nutritional supplements used today, as you may find it isolated, added to multivitamins and in fortified processed foods. While it’s necessary for biological function, too much may do tremendous damage.

In fact, iron overload may be a more common problem, and far more dangerous, than iron deficiency anemia.17 Nearly all adult men and postmenopausal women are at risk for iron overload as there is no clear efficient iron excretion method. In other words, these populations do not lose blood on a regular basis.

Blood loss is the primary way to lower excess iron. If excess iron is left untreated it may contribute to cancer, heart disease, diabetes and neurodegenerative diseases.18 Iron triggers damage by catalyzing a reaction with hydrogen peroxide within the mitochondrial membrane, forming hydroxyl free radicals.

These are among the most damaging free radicals and cause severe mitochondrial dysfunction.19 This in turn is at the heart of many chronic degenerative diseases.

GGT may also be used as a screening marker for excess free iron,20 as it is highly interactive with iron and will tend to raise GGT levels. When your serum ferritin and GGT are high, you have a significantly increased risk of chronic health problems.

Balance Your Omega-3 and Omega-6 Fats for Optimal Liver Function

The American Liver Foundation estimates nearly 25 percent of adults in the U.S. are affected by nonalcoholic fatty liver disease (NAFLD). The condition is associated with serious risks as it may cause the liver to swell (steatohepatitis) and may lead to liver cancer or liver failure.21

It often has no symptoms but may be suspected if you suffer from other associated conditions and your blood tests have high levels of liver enzymes. Progression from NAFLD to nonalcoholic steatohepatitis (NASH) is one of the leading causes of cirrhosis in adults in the U.S.22

Excess amounts of omega-6 fatty acids are challenging to the liver.23 Although both omega-3 and omega-6 are necessary for good health, dietary changes over the past several decades have increased the ratio of omega-6 to omega-3 up to 25-to-1, well above a healthier 5-to-1 ratio, or the 1-to-1 ratio recommended by some experts.24

Experimental studies have suggested this divergence increases your body’s ability to gain fat and, more importantly, increase systemic inflammation. Additionally, the lopsided ratio plays a role in the development of obesity through an increased activity of the cannabinoid system and AA eicosanoid metabolites.25

Researchers have found this process may be reversed by increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both components of marine-based omega-3 fat. Research has also found excessive amounts of damaged omega-6 are associated with inflammatory diseases such as NAFLD, cardiovascular disease, inflammatory bowel disease and Alzheimer’s disease.26

The primary therapeutic action of marine-based omega-3 is reducing inflammation, while omega-6 is needed to initiate the inflammatory response.27 When the ratio is unbalanced in favor of omega-6, it increases the rate of inflammation. Other health benefits associated with a healthy omega-3 to omega-6 ratio include balancing low-density lipoprotein cholesterol and triglyceride levels,28 reducing blood pressure29 and preventing atherosclerosis.30

In addition to reducing the risk of obesity and inflammation, balancing your omega-3 fatty acids against your omega-6 intake can also help reduce your GGT level,31 improve liver fat, reduce triglycerides and improve HDL levels in those with NAFLD or NASH, both inflammatory processes not triggered by alcohol intake.

Cholesterol Profile Reveals Challenges With Insulin Sensitivity

Your liver is responsible for cholesterol regulation, as it not only synthesizes cholesterol but also removes it from your body, converting it to bile salts to be eliminated in your feces.32

When damaged, your liver is unable to regulate cholesterol levels normally.33 This may result in atherogenic dyslipidemia, or elevated levels of triglycerides and LDL, with low levels of high-density lipoprotein (HDL) — levels commonly associated with the development of atherosclerosis plaques and heart disease.34

However, there is also an association between dyslipidemia and insulin resistance.35 Insulin resistance alters lipid metabolism, leading to the development of atherogenic dyslipidemia, contributing to atherosclerotic plaque formation.36

One reason atherogenic dyslipidemia is a predictor of heart disease is because it indicates insulin resistance, which means in some ways your cholesterol panel may tell you more about your insulin resistance and glucose intolerance than anything else.37

Normalize Your Liver Function Naturally

Dr. David Unwin, a low-carb advocate, was voted among the top 50 most influential general practitioners in the U.K. in September 2018.38 In this short video, he discusses the health improvements patients in his practice have experienced, pertaining to insulin resistance and liver function, as they follow a low-carbohydrate diet.

Your carbohydrate intake has an effect on your glucose metabolism, liver function and your risk of heart disease, stroke and Type 2 diabetes. Reducing carbs to 50 grams for every 1,000 calories and increasing your intake of healthy fats is a powerful way to support your mitochondrial health and reduce your risk of chronic disease. Other ways of protecting your liver health include:

Optimizing your omega-3 to omega-6 ratio — Maintaining a balance of omega-6 to omega-3 fats as close to 1-to-1 is ideal. Omega-3 fat may be found in wild caught Alaskan salmon, herring, mackerel and anchovies. Consider using a high quality krill oil supplement if you don’t eat these fatty fish on a regular basis. Reduce or eliminate processed foods, which are high in damaged omega-6 fats, and vegetable oils for cooking.

Giving blood — If you are male or a postmenopausal woman, giving blood twice a year helps lower your iron level and protect your liver from damage.

Exercising — Exercise helps burn triglycerides for fuel and may help reduce liver fat.39

Take N-acetylcysteine (NAC) — This is a precursor to glutathione, a powerful antioxidant that helps reduce oxidative stress and is used in the treatment of chronic fatty liver diseases.40

Avoid medications — Many drugs and hormones are first metabolized through your liver, including birth control and anabolic steroids — in fact, nearly 50 percent of all drugs on the market are metabolized by just one enzyme in the liver.41

Over-the-counter (OTC) medication such as Tylenol and cold and pain remedies are also metabolized through your liver, as are statins, acid blockers, antifungals and certain antibiotics — in all, over 1,000 OTC drugs and herbal medicines have been associated with drug-induced liver injury.42,43

Avoid alcohol if you have NAFLD or NASH — It’s important to drink alcoholic beverages responsibly, however if you already suffer from NAFLD or NASH, alcohol may increase your risk of cirrhosis and destroy your liver cells.44

Optimize your gut — The release of undigested food and bacteria from a leaky gut condition eventually results in liver inflammation. Emerging evidence has suggested a strong relationship between your gut health and your liver.45

Your liver receives nearly 70 percent of its blood supply from the intestines through the portal vein.46 Researchers have also discovered up to 75 percent of those who suffer from chronic liver disease also suffer from microbiome imbalance.47

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Weekly Health Quiz: Glyphosate, Depression and Pain

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1 The following individual has publicly stated he believes children whose parents refuse to vaccinate should become property of the state:

  • Dr. Anthony Fauci, director of NIAID
  • Dr. Paul Offit, chief of the division of infectious diseases at Children’s Hospital of Philadelphia

    Dr. Paul Offit has stated he believes children whose parents refuse to vaccinate should become property of the state. Learn more.

  • Art Caplan, professor of bioethics and head of the division of medical ethics at New York University School of Medicine
  • Dr. Peter Jay Hotez, co-director of the Texas Children’s Hospital Center for Vaccine Development

2 The U.S. childhood vaccination schedule includes the following number vaccine doses:

  • 23 doses of seven vaccines
  • 43 doses of a dozen vaccines
  • 69 doses of 16 vaccines

    In 1983, the U.S. government recommended 23 doses of seven vaccines, given between 2 months and 6 years old. Today, the child vaccination schedule is 69 doses of 16 vaccines, given between the day of birth and age 18, with 50 doses administered before age 6. Learn more.

  • 99 doses of 23 vaccines

3 Which of these four health effects has not been identified as a potential effect of glyphosate exposure?

  • Non-Hodgkin lymphoma
  • Disrupted gut microbiome
  • Impaired protein production
  • Hyperthyroidism

    Glyphosate and glyphosate-based weed killer formulations have been linked to Non-Hodgkin lymphoma, impaired protein production, microbiome disruption, inhibited release of thyroid stimulating hormone, which can lead to hypothyroidism and much more. Learn more.

4 Which of the following is not a possible side effect of antidepressants?

  • Improved heart health

    Antidepressants are neurotoxic and possible side effects include worsening depression, self-harm, violence and suicide, increased risk for diabetes, heart disease, heart attack, stroke and dementia, and depletion of various nutrients (depending on the type of drug you take). Learn more.

  • Worsening depression
  • Self-harm and/or suicide
  • Increased risk for dementia

5 The following statement is accurate:

  • Strength-based exercises are complex and require gym equipment to be beneficial
  • Using nothing but your own body weight you can get a great workout that provides both strength and cardiovascular benefits

    Strength-based exercises do not have to be complex or require a gym in order to be beneficial. Using nothing but your own body weight you can get a great workout. Benefits of bodyweight exercises include efficiency, cardiovascular and strength benefits, improved core strength, flexibility and balance. Learn more.

  • Bodyweight exercises have been proven inefficient
  • Bodyweight exercises provide strength benefits but not cardiovascular benefits

6 How much has the vaccine injury compensation program (VICP) created under the National Childhood Vaccine Injury Act of 1986 paid out in awards for vaccine damage and death?

  • $400 million
  • $40 million
  • $4 billion

    Since its inception in 1986, the vaccine injury compensation program (VICP) has paid out approximately $4 billion in awards for vaccine damage and death. Learn more.

  • $4 million

7 The following treatment may help speed recovery from severe chronic pain:

  • Brain surgery
  • Opioid pain relievers
  • Over-the-counter pain relievers
  • Neurofeedback therapy

    Mark DeBrincat, a chiropractor also known as the “Good News Doctor,” recovered from severe injuries that kept him in severe chronic pain for 15 years using neurofeedback and essential oils. Read about his remarkable return to health here. Learn more.


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Fight Aging! Newsletter, April 8th 2019

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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.

This content is published under the Creative Commons Attribution 4.0 International License. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/


  • Thoughts on Attending Undoing Aging 2019
  • Small Molecule Screening for Longevity Effects in Nematode Worms
  • A Study Observing No Significant Relationship Between Exceptional Longevity and Cardiovascular Risk Factors
  • Senolytic Treatment in Mice Improves Recovery Following Heart Attack
  • Low Mitochondrial Permeability is Required for Autophagy to Extend Life Span
  • Identifying the Source of New Neurons in the Adult Hippocampus
  • Alginate Encapsulation to Ensure Greater Cell Survival Following Transplantation
  • Upregulating ACSL1 Reduces the Impact of Heart Failure in Mice
  • The Life Extension Advocacy Foundation at Undoing Aging 2019
  • CBX4 Upregulation Reduces Cellular Senescence and Osteoarthritis in Mice
  • There is a Large Difference in Mortality Rate Between a Sedentary Lifestyle and Daily Physical Activity
  • Nicotinamide Riboside Reverses Age-Related Decline in Intestinal Stem Cell Populations
  • Mitochondrial Ion Channels in the Mitochondrial Dysfunction that Occurs with Aging
  • Learned Helplessness as a Contribution to the Ubiquitous, Harmful Acceptance of Aging
  • UPD1 Gene Acts on the JAK/STAT Pathway to Regulate Life Span in Flies

Thoughts on Attending Undoing Aging 2019


I recently attended the second Undoing Aging conference in Berlin, the big central conference for our long-standing – and recently greatly expanded – community of researchers, entrepreneurs, investors, and numerous supporters, all engaged in some way in the great project of building the technologies needed for human rejuvenation. This year the event was significantly bigger than last year. The conference was hosted by the Forever Healthy Foundation and the SENS Research Foundation, and is in many ways a platform for spreading and building upon the views of Aubrey de Grey and Michael Greve on aging and how it should be tackled by the medical research and development community. That means addressing the fundamental causes of aging, those outlined in the SENS rejuvenation research programs.

Interestingly, there was a strong Russian contingent present, researchers, venture capitalists, and advocates. They don’t make it out to the US quite so often. I finally met Mikhail Batin, one of the figures behind the Science for Life Extension Foundation and Open Longevity initiatives, whose writing I have noted over the years. I made a small bet with him that senolytics either will or won’t be shown to finally work this year. You can probably guess which side of that wager I took. Like many in the Russian longevity community, he perhaps feels that removal of senescent cells is too simple a strategy in the face of the metabolic complexity of aging. It is a little too trite to say that Russians tend towards a programmed aging viewpoint, but it isn’t entirely incorrect. Targeting points of comparative simplicity, the causes of aging, is of course the SENS rejuvenation research strategy – but as this exchange illustrates, we advocates have yet to convince everyone, even in the community, and even given the stunning technical successes in senolytic studies of recent years.

Among the Russian investors, Andrey Fomenko of IVAO made an appearance to chat to some of the entrepreneurs present, such as Doug Ethell of Leucadia Therapeutics and the Oisin Biotechnologies team. Fomenko is worthy of note here, distinct from several other Russian venture capital folk, for setting up the Eternal Youth Fund, somewhat analogous to some of the funds in the English language world, such as the Longevity Fund or Juvenescence. Jim Mellon of Juvenescence was also present at the conference, of course, with rarely a spare moment to say hello between being pitched on one project for another. Given that he has funded a good fraction of the companies in the rejuvenation biotechnology space at this point in time, this will probably be a good summary of his daily experience for the next decade or so. This is a vigorous growth market.

You’ll have to forgive me for providing few details as to what was actually presented at Undoing Aging, either in posters or the presentations. The science progresses, but these days I am an entrepreneur with my own biotech company working on methods of rejuvenation, and so when I go to conferences it is now the case that I am no longer able to listen to all that many of the presentations. Instead I must pitch investors and network relentlessly. Fortunately, the presentations were recorded, including my outline of how things are going at Repair Biotechnologies with our preclinical work on thymic rejuvenation and reversal of atherosclerosis, and they will be uploaded to YouTube once the technical folk are done with them.

Taken as a whole, a great deal of interesting research and development was announced at the conference, both by startup companies and research groups. Undoing Aging is very much the event to be presenting at if one wants to gain attention for one’s work. Like the upcoming July Ending Age-Related Diseases conference organized by LEAF in New York City, this is a meeting of people with funds and the people who can deploy those funds to make progress towards the goal of the medical control of aging. Transactions take place, and a great deal of new funding is entering this space. Numerous organizations and high net worth individuals are setting up funds devoted to the longevity industry, following Juvenescence, Life Biosciences, and the like, or changing their focus to include this novel area of biotechnology as it expands rapidly. A tipping point has passed, and there is now more than enough seed stage funding out there for anyone with a credible project and team.

One of the topics of discussion that came up several times, with a number of different people, quite independently of one another, is that given the amount of time we advocates spend trying to educate entrepreneurs and investors new to the field, we should produce a bible on how to enter the longevity space, either to start a company, or to fund a company. A good dozen people in our core community, those who have been involved for a decade or more, have had that experience over the past few years, so the memories are still fresh. We don’t have enough entrepreneurs in the present community to tackle even a tiny fraction of all the rejuvenation biotechnology projects that could proceed to preclinical development in a startup, and thus these entrepreneurs must arrive from somewhere, comparatively ignorant. We want them to take up effective projects based on the SENS view of aging, and not be sidetracked into marginal work.

Equally, on the investment side of the house, investors in any field have traditionally had the challenge of identifying high expectation value projects, when the differences between great, merely good, and useless are extremely technical. When it comes to treating aging as a medical condition, there is an enormous chasm between the benefits that might be realized through traditional small molecule tinkering with metabolism (e.g. calorie restriction mimetics) and new approaches that actually reverse the causes of aging (e.g. senolytics). The latter are reliable, have large effects, and progress is comparatively easy. The former are unreliable, have marginal effects, and progress is challenging and expensive. It can take some time to learn enough to be able to determine which of these categories any given therapy falls into.

Thus we, the advocates, definitely need to step up and become more organized. We can’t reach out one by one with a personal connection to every investor and entrepreneur, and carry out an intervention to prevent more marginal initiatives from launching. That doesn’t scale. What we can do is establish a baseline of education and common sense regarding the field, and spread that understanding far and wide. We can thus help newcomers enter the community with enough knowledge to further educate themselves, and to make more sensible choices along the way regarding the projects they undertake.

Of the interesting news from the conference, the SENS Research Foundation is (finally) directly spinning out a for-profit company, rather than only being more indirectly involved in the process of commercializing SENS-related biotechnology. The initiative involves an interesting take on how to get rid of the 7-ketocholesterol that is an important cause of atherosclerosis, spurring the condition by turning macrophages into inflammatory foam cells. The SENS Research Foundation researchers have found a class of molecule that seems fairly innocuous in terms of side-effects and is willing to bind to 7-ketocholesterol and remove it from cells. We will no doubt be hearing more on this later, as the project progresses beyond the setup phase and into properly running as a business and raising venture funding.

It also seems that the Forever Healthy Foundation crowd have the ambition to establish an aging research institution for Berlin after the model of the Buck Institute in California, to work towards making the city a center for aging research as well as all the other items it is famed for. This is a constructive ambition, and the people involved have the connections and the resources to make it happen, given enough time. I look forward to seeing this project make progress. Per a discussion with the Forever Health Foundation principles at the end of the conference, the third Undoing Aging conference next year should prove to be yet bigger than this year’s. The event has outgrown the present venue quite handily, and was forced to turn people away in the final days of registration. These are all signs of success, I hope. Still, it is now up to all of those working on therapies and the foundations of therapies to take the new opportunities for funding, and use that funding make the biotechnologies of repair and rejuvenation a reality. Convincing the investors and philanthropists of the world to fund these goals is just step one in the process.

Small Molecule Screening for Longevity Effects in Nematode Worms


A very large fraction of the research aimed at the production of interventions to slow aging involves some form of screening small molecule compounds for potential effects. There are huge stock libraries of these things, and many well established approaches to carrying out such screening processes. While new ventures are using machine learning to try to make this process far more efficient than is presently the case, after the fashion of In Silico Medicine, I’d say that the future will be a matter of gene therapy making small molecules obsolete. Gene therapy offers the possibility of precise alteration of the gene expression of a rationally chosen target, rather than the uncertainty, serendipity, and off-target effects inherent in small molecule development.

Still, much of the community, particularly the business community, will remain firmly tied to small molecule development programs for the foreseeable future. Researchers will continue to innovate when it comes to novel ways to run such programs. The example here makes use of nematode worms as the screening system: pick a set of compounds, see what they do to worm longevity, then investigate the biochemistry of the successes to understand whether or not they work in the expected fashion, and whether or not the mechanism might be applicable to mammals.

It is worth noting that most such discoveries work via alterations of stress response systems or other aspects of metabolism that do not produce large gains in life span in long-lived species. A doubling or more of nematode life span has been achieved in a variety of ways, but none of those are based on underlying mechanisms that have anywhere near the same effects when triggered in mammals. We need to look elsewhere to achieve that outcome, meaning work on deliberative repair of the underlying causes of aging, rather than adjustment of metabolism to modestly slow aging.

Discovery of life-extension pathway in worms demonstrates new way to study aging

Lifespan studies using C. elegans worms typically involve the deletion or silencing of a particular gene in the embryonic stage of life to see if that extends the average lifespan of affected animals. Researchers took a different approach, using small-molecule compounds to disrupt enzyme-related pathways in adult worms, in the hope that this would uncover pathways that regulate lifespan. The team used a library of about 100 such compounds, all known to inhibit enzymes called serine hydrolases in mammals. “Metabolic processes are very important in determining the rate of aging and lifespan, and serine hydrolases are major metabolic enzymes, so we thought there was a good chance we’d find an important aging-related enzyme this way.”

After finding ways to get the compounds through the tough outer skin of the worms, the researchers tested them on worms that were 1 day into adulthood, and found that some of the compounds extended average worm lifespan by at least 15 percent. One, a carbamate compound called JZL184, extended worm lifespan by 45 percent at the optimal dose. More than half the worms treated with JZL184 were still alive and apparently healthy at 30 days, a time when virtually all untreated worms were dead of old age. JZL184 was originally developed as an inhibitor of the mammalian enzyme monoacylglycerol lipase (MAGL), whose normal job includes the breakdown of a molecule called 2-AG. The latter is an important neurotransmitter and is known as an endocannabinoid because it activates one of the receptors hit by the main psychoactive component in cannabis.

Curiously however, a corresponding MAGL enzyme does not exist in C. elegans worms, so JZL184’s target in these animals was a mystery. Researchers found, though, that one of the main target enzymes for JZL184 in worms was fatty acid amide hydrolase 4 (FAAH-4). Although FAAH-4 and MAGL are not related in terms of their amino-acid sequences or 3-D folds, further experiments revealed, surprisingly, that FAAH-4 in worms does what MAGL does in humans and other mammals: it breaks down 2-AG. 2-AG has been linked to aging in mammals; one recent study found evidence that its levels fall in the brains of aging mice, likely due to greater MAGL activity. The results suggest, then, that studying the FAAH-4/2-AG pathway in worms could one day yield lifespan-extending strategies for humans.

Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan

Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184 – an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL) – as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog.

We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.

A Study Observing No Significant Relationship Between Exceptional Longevity and Cardiovascular Risk Factors


Today’s open access paper illustrates one of the many issues inherent in the study of the biochemistry and genetics of exceptionally long-lived people, which is that the data from various different initiatives rarely agrees. The effects of individual or even groups of gene variants are small and hard to pin down. Past studies have suggested that exceptional longevity is correlated with a lack of cardiovascular risk factors, whether genetic or measured aspects of biochemistry such as lipid levels in blood. That seems a sensible hypothesis: cardiovascular disease removes people from the population, therefore older cohorts should exhibit fewer signs of risk for cardiovascular disease. Yet that is not the case in the work presented here: there is no good association between longevity and lesser presence of risk factors.

What this sort of distribution of results should tell us is that the biochemistry of exceptional human longevity is a poor area of study if the goal is to produce reliable therapies with large effects on human aging. Old people who survive to very late life do so largely because they are either lucky (in exposure to pathogens, in the way in which the damage of aging progressed in a stochastic manner in their case) or because they made good lifestyle choices for much of their span of years. Or both. Beneficial genetic variants and consequent differences in cellular metabolism appear to confer only very modest increases in the odds of living for a long time, and even for those people who do live longer, the impact of degenerative aging is very significant. An environment of small, unreliable effects should be skipped in favor of research strategies with larger potential gains at the end of the day.

Exceptional Longevity and Polygenic Risk for Cardiovascular Health

Exceptional longevity, defined as exceeding the average life expectancy, is multifaceted with genetic, environmental, and epigenetic factors all playing a role. Exceptionally long-lived (ELL) individuals are examples of successful ageing with a proportion demonstrating compression of morbidity. It is important to study these models of successful ageing, as these rare individuals may reveal novel longevity-associated pathways, which may ultimately translate into strategies to promote health in our ageing population.

There is evidence linking healthier cardiovascular risk profiles and lower incidence of cardiovascular disease with longevity. Analysis of lipid metabolism in longevous families identified changes in lipid concentration in the offspring of nonagenarians. Levels of apolipoproteins, important lipid transporters in the circulatory system, have been observed to decline with age. However, higher apolipoprotein levels in the exceptionally long lived have been reported, suggesting a younger apolipoprotein profile that may promote longevity.

Polygenic risk scores (PRS) for cardiovascular-related phenotypes can now be calculated due to the availability of summary data from genome-wide association studies (GWAS) examining a broad range of traits from lipids to coronary artery disease. This facilitates the evaluation of the contribution of polygenic risk for cardiovascular risk factors and disease to exceptional longevity and successful ageing. Thus, the purpose of this study was to explore the genetic profiles of ELL individuals aged (≥95 years) by assessing their polygenic risk for cardiovascular related risk and disease phenotypes relative to middle-aged controls.

This study did not confirm the hypothesis that ELL individuals have lower polygenic risk scores for cardiovascular-related phenotypes. Only the HDL cholesterol and triglyceride PRS were nominally significantly associated with ELL participants. In contrast and as expected, ELL individuals had higher polygenic risk scores for exceptional longevity (EL). In regards to the associations of the various cardiovascular PRS with EL, no findings survived correction for multiple testing. This is despite validating the utility of the lipid PRS by confirming positive associations with measured lipid levels in our sample. Interestingly, the different lipid PRS were based on GWAS that found a large number of genome-wide significant loci. ELL individuals had lower LDL and total cholesterol levels than controls in this study, but they did not differ on their respective PRS. This may suggest that environmental factors, perhaps lifestyle-related, influenced these lipid levels, which possibly promote longevity.

In contrast, the UK Biobank study observed that extreme parental longevity (defined as at least one parent who survived to the top 1% of age at death) had lower polygenic risk for several cardiovascular health measures. Namely coronary artery disease, systolic blood pressure, body mass index, high-density lipoproteins, low-density lipoproteins, and triglycerides. A similar result for HDL cholesterol and extreme parental longevity (EPL) by the UK Biobank to the current study was reported. Again, similar results were reported by the UK Biobank for LDL. However, the observed discrepancies between our analysis and the UK Biobank were most likely due to methodological differences, including the use of PRS that were based on different GWAS.

Senolytic Treatment in Mice Improves Recovery Following Heart Attack


Senescent cells are a cause of aging. They accumulate with the passage of years and decades, a process that is in part just a matter of numbers and averages over time, in which a minuscule fraction of the vast number of newly senescent cells arising every day manage to evade destruction. Importantly, it is also due to the progressive failure of the immune system in its surveillance of errant cells. Senescent cells, like cancer cells, are attacked and destroyed by immune cells, and thus their numbers rise as immune cells become less competent. The harm done by senescent cells is mediated by the wide range of inflammatory, harmful factors that they secrete. The presence of even a small number of senescent cells disrupts tissue function, structure, and regenerative capacity.

As noted in today’s open access paper, the presence of senescence cells is important in the aging of the heart and the rest of the cardiovascular system. Cellular senescence contributes to ventricular hypertrophy, the process by which heart muscle becomes larger and weaker. Senescent cells are also implicated in the fibrosis found to disrupt structure and function of heart tissue; removing senescent cells via senolytic treatment reserves this fibrosis. Further, the chronic inflammation produced by senescent cells is generally harmful to the cardiovascular system, contributing to the progression of arterial stiffening via smooth muscle cell dysfunction, and atherosclerosis via macrophage dysfunction.

Senescent cells actively enforce their contribution to the state of aging via their secretions. Remove the cells, and that contribution vanishes, leaving behind downstream damage that can be repaired by cell populations to a sizable degree. Senolytic therapies to clear senescent cells have been demonstrated to extend life in mice, and turn back the progression of many aspects of aging and age-related diseases. Targeted destruction of senescent cells is a rejuvenation therapy, albeit a narrowly focused form of rejuvenation, targeting only one of many forms of damage that cause aging. The work here is one of many papers to demonstrate this point.

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction

Cellular senescence is classically defined as the irreversible cell cycle arrest of somatic cells. While senescence can act as a potent antitumour mechanism, recent studies have shown that senescent cells accumulate in several tissues with age where they contribute to age-dependent tissue dysfunction and several age-related diseases. Senescent cells are thought to contribute to aging via a pro-oxidant phenotype and the secretion of a senescence-associated secretory phenotype (SASP), which is pro-inflammatory, profibrotic, and can also promote senescence in surrounding cells.

Senescence has been shown to occur in the heart during aging and contributes to the pathophysiology of a number of cardiovascular diseases, as clearance of senescent cells in aged and atherosclerotic mice using both genetic and pharmacological approaches improves vascular and myocardial function and attenuates age-dependent remodelling. However, the impact of senescent cells in myocardial infarction (MI) has not been investigated thus far. In this study, we hypothesise that senescent cells contribute to the poor prognosis and survival of aged individuals following MI. Previously we found that in addition to clearing senescent cells, navitoclax treatment reduced fibrosis and cardiomyocyte (CM) hypertrophy in aged mice and considered that these beneficial effects may help to improve outcomes in aged mice following MI. We therefore performed a more detailed longitudinal study to examine this possibility and to explore potential mechanisms.

Histological analysis was performed on a cohort of noninfarcted mice, to assess the baseline effects of navitoclax treatment. In addition to decreasing CM hypertrophy, treatment reduced markers of CM senescence, indicating clearance of senescent cells from the hearts of treated aged mice. Furthermore, we found a significant reduction in expression of profibrotic TGFβ2, which we previously identified as a key component of CM SASP. Functionally, navitoclax treatment significantly reduced the age-dependent increase in left ventricular (LV) mass but did not impact on ejection fraction (EF). Aged mice also exhibited a decrease in the percentage change in diastole versus end systole LV wall thickness, indicating an increased LV rigidity compared with young animals, which was also partly rescued by navitoclax treatment. Clinically, increased ventricle stiffness is related to fibrosis and hypertrophy during aging, is symptomatic of diastolic dysfunction and is observed in heart failure with preserved ejection fraction patients.

We observed that aged mice had significantly higher mortality rates following MI (60% over 5 weeks) compared with young mice and that this outcome was rescued by prior navitoclax treatment. In contrast to young mice, old mice show a significant reduction in EF between 1 and 4 weeks post-MI. Importantly, navitoclax was able to rescue this functional decline which may help to explain the improved survival of this group. Furthermore, expression of senescence markers p16 and p21 at 4 weeks following MI was reduced in the hearts of navitoclax-treated mice, consistent with reduction of the senescence burden.

Collectively, this study shows that pharmacological clearance of senescent cells in aging mice alleviates age-dependent myocardial remodelling and attenuates expression of profibrotic mediators. Navitoclax improved the maintenance of cardiac function following MI, ultimately increasing survival. An important limitation of this study is that our experimental strategy was not able to distinguish which senescent cell types are responsible for this effect, and it is possible that clearance of senescent cells in noncardiac organs impact on survival following MI. We have focussed our attention on CMs in this study as our earlier findings showed that, in the heart, markers of senescence accumulate primarily in CMs during aging. However, further studies using animal models where senescent cells can be cleared in a cell-type specific manner are required to formally show the contribution of senescent CMs to cardiac recovery post-MI.

Low Mitochondrial Permeability is Required for Autophagy to Extend Life Span


Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP) that powers cellular processes. Every cell possesses a herd of mitochondria, replicating like bacteria, and monitored by quality control mechanisms. Damaged, potentially harmful mitochondria are removed and dismantled for raw materials through a variant of autophagy called mitophagy. A mountain of evidence links mitochondrial function to aging, just as a mountain of evidence links the cellular recycling mechanisms of autophagy to aging. Both mitochondrial function and autophagic activity decline with age, producing downstream consequences that contribute to age-related diseases. There is the strong suspicion, with evidence to back it up, that it is the quality control of mitochondria, and thus maintenance of mitochondrial function without harmful side-effects resulting from damaged mitochondria, that is the common factor here.

Enhanced autophagy is a feature common to many of the methods by which aging can be slowed and life span extended in short-lived laboratory species. Most of these work via upregulation of cellular stress responses – to heat, lack of nutrients, oxidative damage, and so forth – and autophagy is an important stress response mechanism, making cells more resilient. Minor or short stresses lead to a longer upregulation of the response to stress, and thus the overall result is an improvement in health and longevity. This is called hormesis, and is a major part of the way in which intermittent fasting or calorie restriction work. Researchers have in the past demonstrated that calorie restriction actually fails to extend life in animals in which autophagy is disabled.

The topic for today is specifically the permeability of the mitochondrial membrane and its role in the relationship between mitochondrial function and autophagy. A fair amount of attention has been directed in recent years towards the mitochondrial permeability transition pore structures in the mitochondrial membrane, and their role in mitochondrial dysfunction. Clearly greater pore activity and thus greater permeability are a feature of aging, alongside mitochondrial dysfunction, but joining the dots on what is cause and what is consequence in our biochemistry is far from simple. It is known that mitophagy falters in later life, and it is known that this appears to be at least partly a consequence of reduced levels of mitochondrial fission – but consider how long it took to join just those two items. Why do mitochondrial fission rates fall? How does that relate to permeability and the membrane structures that support it? The complexity is overwhelming, which is perhaps why the path forward towards near term therapies is usually to cut the Gordian knot in some way, bypass the system that is poorly understood. Many of the SENS-style proposed rejuvenation therapies based on repair of underlying damage are of this form.

Mitochondrial permeability plays a key role in aging, recovery from ischemic injury

The ability of molecules to pass through the membrane of mitochondria – the cellular structures that convert nutrients into energy – may determine whether or not autophagy, a cellular process that removes damaged and dysfunctional molecules and cellular components, is beneficial or detrimental to the health of an organism. As the accumulation of damaged molecules and defective proteins is considered a hallmark of aging, autophagy has been associated with increased longevity. In fact, model organisms in which gene mutations or measures such as calorie restriction lead to lifespan extension depend on autophagy for their beneficial effects. However, autophagy can also play a role in cancer, diabetes, neurodegeneration and in the ischemia/reperfusion injury caused by restricted blood flow.

Previous studies have suggested that inhibition of the mTORC2 molecular pathway, which controls several critical metabolic functions, shortens lifespan. Organisms in which mutations in mTORC2 or in the gene encoding its downstream effector protein SGK-1 have reduced lifespan also show increased autophagy. Experiments revealed that inhibition of autophagy can restore a normal lifespan in mTORC2/SGK1 mutant C. elegans roundworms. The researchers also found that SGK-1 can regulate the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. Excessive opening of the mPTP, either by inhibition of the mTORC2/SGK-1 pathway or by direct genetic stimulation, transforms autophagy from a beneficial to a detrimental function, resulting in a shortened lifespan. Overall, the results indicate that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.

Since autophagy is believed to contribute to ischemic injury, the investigators looked at its potential role in ischemia/reperfusion (I/R) injury – the exacerbation of tissue damage that occurs when blood flow is restored to tissue to which it had been restricted. They found that mice in which expression of the gene for SGK-1 was knocked out in the liver were more susceptible to I/R injury of the liver than were unmutated animals. While both current and previous research has indicated that elevated autophagy and mitochondrial permeability are harmful in the early phases of reperfusion injury, autophagy may help reduce the severity of tissue damage at later stages when damaged cellular components must be cleared from the cell.

Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension

Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.

Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

Identifying the Source of New Neurons in the Adult Hippocampus


Following on from recent confirmation of adult neurogenesis in humans, researchers here report on the identification of the stem cell population responsible for supplying neurons to the hippocampus in mice. The process by which new neurons are created and integrated into neural networks is considered an important target for future regenerative therapies. If the pace can be increased in older individuals, it may go some way towards reversing aspects of age-related cognitive decline, or enhance recovery after brain injury. Characterizing the stem cells responsible for creation of new neurons is an important step on the road towards targeted, selective upregulation of neurogenesis.

It was once believed that mammals were born with the entire supply of neurons they would have for a lifetime. However, over the past few decades, neuroscientists have found that at least two brain regions – the centers of the sense of smell and the hippocampus, the seat of learning and memory – grow new neurons throughout life. Researchers have now shown, in mice, that one type of stem cell that makes adult neurons is the source of this lifetime stock of new cells in the hippocampus. These findings may help neuroscientists figure out how to maintain youthful conditions for learning and memory, and repair and regenerate parts of the brain after injury and aging.

The researchers showed that the neural stem cells they found had a common molecular signature across the lifespan of the mice. They did this by labeling neural stem cells in embryos when the brain was still developing and following the cells from birth into adulthood. This approach revealed that new neural stem cells with their precursor’s label were continuously making neurons throughout an animal’s lifetime. This capacity is called plasticity, which is the brain’s ability to form new connections throughout life to compensate for injury and disease and to adjust in response to new input from the environment. The next step for the researchers is to look for the same neural stem cells in other mammals, most importantly in humans, starting the search in post-mortem brain tissue, and to investigate how this population of neural stem cells are regulated.

Alginate Encapsulation to Ensure Greater Cell Survival Following Transplantation


Many sorts of cell therapy work because of the signals secreted by the transplanted cells. In most cases, near all such cells die quite quickly, failing to integrate into the recipient tissue. Methods of reliably improving cell survival could be used to make these first generation therapies more effective, but more importantly enable a whole range of second generation therapies that are presently impractical. One approach that seems to be gaining traction is to generate a tissue-like structure in which cells are better supported, and transplant that: heart patches are an example of the type. Another approach is outlined here, in which transplanted cells are encapsulated in alginate, an approach that protects and supports them sufficiently well to allow regenerative therapies, such as the example here involving the use of macrophages to spur regeneration, to become a practical concern.

Researchers have made small capsules from brown algae which hold macrophages, a type of white blood cell. Tests in mice have shown that these algae capsules may be able to increase blood flow in the limbs where tissue has been damaged. The researchers now hope to move this research into human clinical trials to help the people visiting hospital with critical limb ischaemia (CLI). Scientists have been experimenting with cells as a treatment to grow arteries in the leg for years, however, these treatments have not been effective in humans. A big challenge is that many of the cells injected into the injured area die, move away to surrounding areas, or are detected as ‘foreign’ by the immune system and rejected.

In this study, scientists delivered the new algae-based capsules containing macrophages to areas of injured muscle tissue in the back legs of mice. Alginate from the cell walls of brown algae, which is mainly found in cold waters in the Northern Hemisphere, was used to form the capsules. They found that these macrophages successfully remained in the injured area, new blood vessels formed, and as a result more blood reached the damaged area. Currently, to treat CLI and restore blood flow in the limbs, the blocked section of the artery has to be either bypassed during surgery or widened using a small piece of expandable mesh called a stent. However, in up to a third of patients, these methods will eventually fail or are not possible to begin with and amputation is the only option. The researchers therefore hope that this new way of delivering cells could be the key to creating an effective treatment for people suffering with CLI.

Upregulating ACSL1 Reduces the Impact of Heart Failure in Mice


Metabolism in heart tissue is disrupted in a number of ways in patients with heart failure. Researchers here followed up on the suspicion that fat metabolism is important in this context. They attempt a genetic modification in mice that compensates for just one of the observed changes in how heart tissue manages (or perhaps mismanages) the adaptation to increased stress, namely the much reduced levels of acyl-CoA. They find that this helps. This may or may not lead to a compensatory therapy that strives to make the end stage disease state less terrible, something that I’ve always thought is a less desirable development strategy, comparing unfavorably to attempts to repair the underlying causes of the condition. It may, however, have more significance as an assessment of the degree to which metabolic disruption of this nature is important in the progression of heart failure.

Before any physical signs or symptoms of heart failure are present, the first maladaptive changes occur in cardiac cell metabolism – how the heart fuels itself to pump blood through the body constantly. Our hearts burn fuel, much like combustion engines in cars. Instead of gasoline, our heart cells burn fats and a small amount of glucose. When our hearts become chronically stressed, they try to adapt, but some of those changes make things worse.

Researchers examined both mouse models of heart failure and human heart tissue obtained from heart failure patients before and after heart assist devices were surgically implanted. They found that the amount of a reactive fat compound, called acyl-CoA, is nearly 60 percent lower in failing hearts compared to normal hearts. This disruption in the heart’s normal metabolism creates toxic fats that impair the heart’s ability to function and pump properly. Then the team tested mice that overexpressed a gene for a protein called ACSL1, that’s known to make acyl-CoA. When exposed to conditions that cause heart failure, the mice kept making normal amounts of acyl-CoA and the extent of heart failure was reduced and delayed.

By maintaining this fat compound, acyl-CoA, the hearts retained their ability to burn fat and generate energy. Importantly, overexpression of ACSL1 also reduced toxic fats, normalized cell function, and reduced the progressive loss of function in the enlarged mouse hearts. When the team examined failing human hearts that had the help of a left ventricular assist device (LVAD), they found similar effects – the levels of acyl-CoA had restored to normal when the sick hearts didn’t have to work beyond their capacity. “This tells us there’s an important relationship between fat metabolism in the heart and the inability to pump well, and we need to learn more. We believe targeting the normalization of acyl-CoA is a new approach to explore.” Next, the team wants to explore how normalizing acyl-CoA helps reduce toxic fats and increase protective fats inside the heart. Soon, they hope to use advanced imaging to track fat metabolism and function in patients’ hearts.

The Life Extension Advocacy Foundation at Undoing Aging 2019


The Life Extension Advocacy Foundation (LEAF) volunteers were all at the Undoing Aging conference in Berlin this last week. Given that they, like most of the insiders, were spending much of their time interviewing and networking, they are little better a source than I am when it comes to reporting on the actual content of the presentations and announcements. Clearly we need to assign someone with a notepad to a seat next year, and make sure he or she stays there. The LEAF folk carried out a great many interviews, and we’ll no doubt see those posted in the weeks ahead.

The atmosphere of the event was very much friendly and informal, with plenty of opportunities to join conversations with researchers and advocates during the breaks while having a bite or a drink. The lineup of speakers included many big names, including Mike West, Judith Campisi, Vadim Gladyshev, Jerry Shay, Nir Barzilai, Kelsey Moody, Julie Andersen, and Ruby Yanru Chen-Tsai. Everyone I asked said that the presentations were all top notch, but I can’t really say anything about them, given that I spent nearly every moment of my stay running after researchers who were being pulled left and right by people who needed to meet them for whatever reason.

Even though I’d gotten used to asking people for interviews fairly quickly, it still felt funny to have breakfast every morning while Nir Barzilai was sitting with other researchers a few tables away, hearing the unmistakable voice of Aubrey de Grey as he entered the room, or knowing that I could easily bump into, say, MitoSENS lead Matthew O’Connor, as I walked around the hotel. Speaking of MitoSENS, at the end of her talk, Dr. Amutha Boominathan mentioned the upcoming MitoSENS 2 campaign on Lifespan.io, which will be aimed at testing allotopic expression in mice, providing proof of concept that the technique can work in mammals; in other SENS news, during the conference, Aubrey de Grey announced the tenth anniversary of the SENS Research Foundation, and a shiny new website was recently launched in celebration.

Personally, I think the best part of Undoing Aging 2019 was the feeling of being together with so many like-minded people who all agree that aging can and should be defeated; they may all have different reasons to want to see the end of aging, and they may even have different opinions on how and when this will be accomplished, but they’re all working together, each in his or her own way, to achieve this common goal. It was heartening to see that they all agree that aging can be brought to its knees, even if they might disagree on methodologies and timeframes; their optimism is what we need to convince the public that a life without aging isn’t a pipe dream anymore.

CBX4 Upregulation Reduces Cellular Senescence and Osteoarthritis in Mice


Cellular senescence is one of the causes of aging; the inflammatory signals generated by growing numbers of senescent cells disrupt tissue maintenance and cell function, and play an important role in many age-related conditions, including osteoarthritis. The best approach to senescent cells appears to be the simple one: destroy them. They accumulate slowly, and therapies that selectively remove senescent cells have been shown in animal studies to produce significant reversal of numerous aspects of aging. Nonetheless, many research groups are more interested in preventing or modulating senescence, with the open access paper here an example of the former. To my eyes, therapies that have to be taken over decades to slow the accumulation of senescent cells are a very poor second best to methods of immediate clearance of these cells.

Stem cell senescence contributes to stem cell exhaustion, a major cause of physiological and pathological aging. Mesenchymal stem cells (MSCs) are adult multipotent cells in various mesodermal tissues that are capable of differentiating into mature cells such as osteoblasts, chondrocytes, and adipocytes. Both physiologically aged individuals and patients with premature aging syndromes exhibit functional degeneration in mesodermal tissues, along with exhaustion of MSC populations, thus characterized by atherosclerosis, osteoporosis, osteoarthritis, etc.

CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. In this study, we reported that CBX4 was downregulated during human MSC (hMSC) senescence and accordingly investigated the role of CBX4 in maintaining cellular homeostasis in hMSCs. Targeted CBX4 depletion in hMSCs resulted in loss of nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein synthesis, and accelerated cellular aging. CBX4 overexpression alleviated senescent phenotypes in both physiologically and pathologically aged hMSCs.

More importantly, lentiviral vector-mediated CBX4 overexpression attenuated the development of osteoarthritis in mice. We demonstrate that CBX4 safeguards hMSCs against cellular senescence through the regulation of nucleolar architecture and function, suggesting a target for therapeutic interventions against aging-associated disorders.

There is a Large Difference in Mortality Rate Between a Sedentary Lifestyle and Daily Physical Activity


Exercise, like all interventions that improve health, has a dose-response curve. As in most such curves, the initial difference between no treatment (a sedentary or near-sedentary lifestyle) and some treatment (moderate physical activity every day) is quite large. Further increments in activity can add increasing benefits, but ever less as activity time increases further. There is an optimal point at which one can be fairly certain of capturing most of the benefits, even given the usual uncertainties in measurement and variation in the response of individuals. For aerobic exercise, and the average human being, the optimal point is probably a greater amount of time than the 30 minutes daily presently recommended.

Regular moderate- to vigorous-intensity physical activity (MVPA) is associated with a lower risk of cardiovascular disease; certain cancers; and premature death. In addition, the amount of time spent sedentary – distinct from physical inactivity – is associated with a higher risk of death and disease. That may be a result, at least in part, from sedentary behavior displacing physical activity.

Most previous studies have explored the potential effect of sedentary time without considering the physical activity it displaces, leaving a gap in the understanding of the issue. To explore further, investigators analyzed self-reported sitting time, light physical activity, and moderate/vigorous physical activity among 92,541 participants in the ACS’s Cancer Prevention Study II Nutrition Cohort.

The analysis reviewed sedentary time and activity levels over 14 years. It found among those who were the least active at baseline (less than 17 minutes/day moderate to vigorous physical activity), replacing 30 minutes/day of sitting with light physical activity was associated with a 14% reduced risk of death, while replacement with moderate to vigorous physical activity was associated with a 45% reduced risk of death.

The investigators found similar but smaller associations among moderately active participants: replacing a half hour of sedentary time with light physical activity was associated with a 6% reduction in mortality among those who were moderately active; replacing 30 minutes of sitting time with moderate to vigorous physical activity was associated with a 17% mortality reduction in this group. However, for the most active (more than 38 minutes/day of MVPA), substitution of sitting time with light physical activity or MVPA was not associated with a reduction in mortality risk.

Nicotinamide Riboside Reverses Age-Related Decline in Intestinal Stem Cell Populations


Nicotinamide riboside supplementation is one of the ways to increase levels of NAD+ in mitochondria, thus improving mitochondrial function. This probably does little for young people, particularly young and physically fit people, but in old age NAD+ levels decline along with mitochondrial function. Mitochondria are the power plants of the cell, and with aging they suffer a general malaise that is detrimental to tissue function, especially in energy-hungry tissues such as muscles and the brain. The causes are still poorly understood, though a faltering of the quality control mechanism of mitophagy due to loss of mitochondrial fission appears to be involved. Increased NAD+ appears to override this decline to some degree, albeit without addressing any of the underlying and still problematic root causes.

In early human trials, NAD+ upregulation has been shown to modestly improve vascular function in older individuals, most likely by reversing some of the dysfunction in smooth muscle cell behavior. In mice a broader range of benefits has been demonstrated, though it remains to be seen how many of those also appear in humans to a significant degree. The work here is more along the same lines, in which researchers show that nicotinamide riboside supplementation can restore intestinal stem cell function in older mice. This should improve tissue function, but again it is worth bearing in mind that this is only overriding a reaction to the underlying damage of aging – it doesn’t fix that damage, which still carries on to produce all of its other downstream issues.

Researchers have long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction. In 2016 it was found that, in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In a new study, researchers set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals. “That has real implications for health. Just having more stem cells is all well and good, but it might not equate to anything in the real world. Knowing that the guts are actually more stress-resistant if they’re NR-supplemented is pretty interesting.”

Mitochondrial Ion Channels in the Mitochondrial Dysfunction that Occurs with Aging


Mitochondria are the power plants of the cell, present by the hundred in near every cell type in the body. They are important in many fundamental cellular processes, but their primary task is to package chemical energy stores in the form of adenosine triphosphate (ATP). Mitochondrial function declines with age in all tissues, and this is particularly problematic in energy-hungry tissues such as the brain and muscles. The cause of this decline may be failure of the quality control mechanisms of mitophagy, responsible for dismantling damaged mitochondria, or it may have deeper roots, such as loss of capacity for mitochondrial fission. Until some of those possible roots can be fixed reliably, it will be hard to assign relative importance to their contributions.

Given that mitochondrial function declines across the board, it will not be surprising to find that any given mechanism exhibits problems in older individuals. Mitochondria are wrapped in membranes, and those membranes use ion channels to pass various ions essential to their operation, such as calcium, back and forth. The open access paper here examines age-related mitochondrial dysfunction through the lens of ion channels and disruption of their activity. This seems likely a downstream issue, but as ever it is quite hard to determine cause and consequence in the mechanisms associated with aging without the ability to reliably intervene to fix just one thing in isolation.

Mitochondria are often referred to as the powerhouse of the cell, however, their physiological role goes well beyond that Mitochondria are highly dynamic organelles regulating their structure in line with metabolism, redox signaling, mitochondrial DNA maintenance, and apoptosis. Besides from generating adenosine triphosphate (ATP) for cellular energy, mitochondria are also deeply involved in providing intermediates for cellular signaling and proliferation. Mitochondria can alter their size and organization as a result of mitochondrial fission and fusion in response to various intracellular and extracellular signals. Fission and fusion events occur to meet metabolic demands and for the removal of damaged/dysfunction mitochondria. The role of mitochondrial fission and fusion in facilitating metabolism has been researched extensively. Fused mitochondrial networks typically engage more oxidative pathways of metabolism, whilst fragmentation as a result of stress impairs the oxidative pathway and increases cellular demand on glycolysis.

Ion channels are intimately involved in regulating mitochondrial function. The essential role of cationic hydrogen (H+) ion transfer in ATP production was noted as early as 1961. H+ ions are pumped from the mitochondrial matrix into the intermembrane space by the flow of electrons through the electron transport chain. These ions are then utilized to drive the ATPase machinery and phosphorylate ATP, thus creating energy for the cell. The movement of ions across the mitochondrial membrane is also essential in establishing membrane potential and maintaining proton (H+) flux. Ions transported across the inner membrane include potassium (K+), sodium (Na+) and calcium (Ca2+), alongside H+. The most well-studied ion channel within the mitochondrion is the voltage-dependent anion channel, VDAC, which is the primary route of metabolite and ion exchange across the outer mitochondrial membrane.

Mitochondrial channelopathies have been found in aging, affecting the K+, Ca2+, VDAC and permeability transition pore (Ca2+; PTP) channels. Mitochondrial Ca2+ cycling is impaired with aging in neurons, resulting from reduced Ca2+ channel activity and reduced recovery after synaptosomal stimulation. This reduced calcium recovery rate results in reduced mitochondrial membrane potential and delayed repolarization, causing mitochondrial dysfunction with aging. This effect has been found in the heart of 2 year old senescent rats. In terms of potassium channels, it has been shown that their density on the surface of mitochondria significantly declines with age and with metabolic syndromes in the heart sarcolemma. This has been shown to reduce tolerance to ischemia-reperfusion and increased injury in aged guinea pig and rat hearts, and also humans.

These effects have repercussions in increasing susceptibility to myocardial infarction and reducing neuronal activity in the elderly as mitochondrial K+ channels have been shown to play a neuroprotective role in neurological reperfusion injury in postnatal mouse pups. Amyloid-β plaques in Alzheimer’s disease have been shown to increase intracellular calcium levels. This increase in intracellular calcium, and uptake into the mitochondria through the VDAC and calcium uniporter, has been shown to increase mitochondrial stress responses and initiate apoptosis in rat cortical neurons in vitro and hippocampal slices ex vivo. Recent studies in Parkinson’s disease, have revealed that α-synuclein acts via the VDAC to promote mitochondrial toxicity of respiratory chain components in a yeast model of Parkinson’s.

Learned Helplessness as a Contribution to the Ubiquitous, Harmful Acceptance of Aging


In a world in which nothing can be done about aging and inevitable death, acceptance is necessary. To remain sane and productive, to work towards a golden future that we will not live to see, requires a stoic viewpoint. One must accept the aspects of the world that are beyond control, and understand that we can control our own reactions to those aspects, so as to lead the best possible life under the circumstances. Aging has long been an aspect of the world beyond our control; one could endeavor to be more healthy rather than less healthy, but in the end there was still the inevitable decrepitude, suffering, and death.

Yet now biotechnology offers the near future possibility of the medical control of aging – and even today, the first rejuvenation therapies, those that selectively destroy senescent cells, are already available to anyone adventurous enough to try. In this environment, where funding, support, and the will to progress are all required to build out the full portfolio of means of human rejuvenation, acceptance of aging has become harmful and poisonous. It holds us back, and tens of millions of lives are the cost of every significant delay.

When you are repeatedly subjected to an unpleasant or painful situation over which you seem to have no control, there comes a point past which you simply give up on the very idea that you could possibly escape your predicament. Once you learn that you’re helpless in the face of circumstances beyond your control, you could end up simply accepting what is happening to you, even when the circumstances have changed enough to offer a way out.

We find this relevant because this learned helplessness could play a role in the pro-aging trance – or, at least, what happens in people’s minds because of the pro-aging trance is very much reminiscent of learned helplessness. If you’re new around here and have no idea what the pro-aging trance is, it’s basically one of the main drivers of irrational opposition to rejuvenation therapies; it’s the groundless conviction that aging is a blessing in disguise and that the fact that people age to death is actually good, despite the overwhelming, blatant evidence that this is not the case.

Even though you don’t spend your entire life with worsening eyesight, diabetes, cancer, or heart disease (to name but a few), you – like everyone else on the planet – were brought up with the notions that aging is inevitable and that one day it will kill you if nothing else does it first. You’re accustomed to the thought that, as you age, you will lose your health to at least some extent, and you have an idea of what you might be like in old age – weak, hunched over, easily fatigued, and with feeble senses and, if you’re unlucky, even more serious health problems. This idea is woven into every fiber of our society, arts, and institutions; even if you’re not exposed directly to the ailments of aging for most of your life, you are exposed to the unpleasant thought that your clock is ticking – a clock that measures not just the time you have left but also your remaining health – and that there’s no way that you could ever stop the clock.

In other words, you spend your entire life with the knowledge that your health is slowly declining, a decidedly unpleasant thing that, ultimately, you have no power to prevent. Therefore, you learn to accept it and make your peace with it, perhaps whimpering about it every now and again, but doing nothing else about it. Once the effects of aging manifest themselves in your old age, the feeling of helplessness gets even more real, as your health problems are no longer hypothetical and your doctor can essentially only help you manage your symptoms. This overall situation has much in common with the definition of learned helplessness.

UPD1 Gene Acts on the JAK/STAT Pathway to Regulate Life Span in Flies


The data presented in this open access paper provides a good example of the complexity of the metabolic processes that influence life span. The researchers overexpress the UPD1 gene in various different tissues in flies. While the UPD1 protein acts via the JAK/STAT pathway in each case, the results on fly life span are wildly different. This sort of thing is exactly why it is very challenging, very slow, and very expensive to try to even modestly slow aging by tinkering with the operation of metabolism, to make an organism more resilient to the damage of aging. There are far better ways forward than this, notably those that involve periodic repair of the damage of aging.

The JAK/STAT signaling pathway is involved in many aging-related cellular functions. However, effects of overexpression of genes controlling JAK/STAT signal transduction on longevity of model organisms have not been studied. Here we evaluate the effect of overexpression of the unpaired 1 (upd1) gene, which encodes an activating ligand for JAK/STAT pathway, on the lifespan of Drosophila melanogaster.

Overexpression of upd1 in the intestine caused a pronounced shortening of the median lifespan by 54.1% in males and 18.9% in females, and the age of 90% mortality by 40.9% in males and 19.1% in females. In fat body and in nervous system of male flies, an induction of upd1 overexpression increased the age of 90% mortality and median lifespan, respectively. An increase in upd1 expression enhanced mRNA levels of the JAK/STAT target genes domeless and Socs36E.

Conditional overexpression of upd1 in different tissues of Drosophila induces pro-aging or pro-longevity effects in tissue-dependent manner. The effects of upd1 overexpression on lifespan are accompanied by the transcription activation of genes for the components of JAK/STAT pathway. As the JAK/STAT pathway is evolutionarily conserved it may be possible to discover compounds that fit the criteria of geroprotector. In our future work we plan to test the compounds from DrugAge and geroprotectors.org and other libraries potentially modulating upd, domeless and Socs36E on the lifespan of Drosophila and other organisms.

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Natural Ways to Lower Blood Pressure

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Benefits of Arginine

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There are several advantages of Arginine. Scientific reports have confirmed several of the benefits that are related to arginine from lowering blood pressure, improving the immune system, reducing arrhythmia symptoms, decreasing bad cholesterol, improving memory, and improving overall cardiovascular health and wellness. This outstanding healthy amino acid is able to boost numerous facets of our

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The Natural Heart Disease Solution

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Here is a list of Heart Supplements that have been shown to support cardiovascular health Arginine and Heart Disease Citrulline and Heart Disease Vitamin D3 and Heart Disease Cardio Cocktail Combats Heart Disease Heart disease is a term we use to cover a vast array of illnesses. It may include cardiac arrest, stroke, arrhythmias, high

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Excited About Weight Loss

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If you are overweight you already know the importance of dieting to lose the extra pounds. You have no doubt heard it many times from your health care professional or you have seen it in the news. Unfortunately knowing you need to lose weight and actually losing weight are two separate mindsets. Weight loss Hurdles

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Can Erectile Dysfunction be Reversed?

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So you wound up here because you’re wondering if erectile dysfunction can be reversed, right?

Well, the answer to this question is a definite yes….in Most cases.

The bigger question is, how difficult will it be to achieve the results you’re looking for?

As you’ll discover below, this will depend on the reason you’re having erection difficulties in the first place.

For example, if you have porn induced ED, the solution is simple. You just need to commit to breaking the addiction and your wood will eventually return.

On the other hand….

If you have severe vascular issues, it’s going to take more time and energy to reverse the situation, but if you attack the problem aggressively, you can definitely improve your situation.

Now here’s David Jaynes with all the details on how to make it happen…

How to Reverse ED

Image of penis anatomy

So you have ED. That sucks, but it’s not the end of the world.

It’s not even the end of your sex life.

Truth is, unless you’re on your deathbed and about to take the Grim Reaper’s hand, you can improve the hardness, frequency, and duration of your erections. It’s just a matter of making a plan, then working it.

Here are a few of the best ways to do it.

1: Clear Your Pipes to Reverse ED

Blood flow is the core physical component of how your penis gets and stays hard. Anything that impacts blood flow will also impact your erections. Penile plaque impacts blood flow.

When the collagen in your blood vessels breaks down, your body patches it up with calcium. That calcium accumulates and leaves deposits that harden and narrow the vessels and reduce blood flow.

It’s a lot like how the pipes in your house accumulate that nasty residue on their interior walls, and need a snake or Drano treatment every few years.

If the blood vessels in and around your penis accumulate too much plaque, that reduces how much blood gets to your penis…which reduces the strength of your erections.

Use the Linus Pauling Protocol to reduce that plaque.

The protocol was developed by Dr. Linus Pauling, a scientist who investigated the role of vitamins in cardiovascular health. He was kind of a big deal before his death in 1994.

He’s just one of four people to have won more than one Nobel prize.

Pauling’s protocol addresses arterial plaque in general throughout the body, but “throughout the body” includes your penis.

To follow the protocol, you take Vitamin C, L-Lysine, and L-Proline.

These three supplements combine to help clean out the plaque in your blood vessels. That helps with your ED, with the added extra bonus of reducing your chances for things like high blood pressure, heart disease, and strokes.

How does it work? I’m glad you asked.

The key here is building and protecting collagen production. That means healthier, more elastic blood vessels, and better blood flow.

  • Vitamin C is the basic building block in lysyl hydroxylase, the enzyme your body needs to make collagen in the first place.
  • L-Lysine and L-Proline are two of the three amino acids your body builds collagen out of. Your body creates  plenty of the third (L-Glycine) on its own. The other two you have to ingest.

The Bottom Line: Take Vitamin C, L-Lysine and L-Proline every day to give your body what it needs to reduce arterial plaque in your member. This will improve blood flow and makes your erections harder.

Learn more about reducing penile plaque and the Linus Pauling protocol here.

2: Eliminate Porn to Reverse ED

Here’s the truth about pornography, no matter what your favorite priests, moms, and feminists might have told you…

It won’t make you blind. It won’t put hair on your palms. It’s not inherently evil, or disgusting. It’s not just for losers who can’t get laid.

But it can give you erectile dysfunction, or make your existing ED worse.

Which, come to think of it, does mean you won’t be able to get laid.

With the internet giving us all an endless supply of not just porn, but the most specialized porn anybody can ask for, this cause of erectile dysfunction is definitely on the rise.

That’s why I talk about it a lot. I mean, a lot.

You can read the links I just dropped for full details on the how and the why of masturbating to porn can simply wreck your sex life.

For now, here’s a quick list of proven ways it does that:

  • Masturbation to pornography can reduce your sensitivity to dopamine, which your brain needs to become sexually aroused
  • Too much porn leads to the “Coolidge Effect” where your brain needs excessive variety in order to get horny, which can lead to erection problems under normal sexual circumstances
  • Masturbating instead of sex can cause all manner of relationship issues, leading to ED from relationship stress.
  • Penis size and women’s reactions in porn can give you an unrealistic expectation for your appearance, size, and performance…which can mean performance-induced erectile dysfunction.

That’s the bad news. But there is good news.

You can just quit. The damage isn’t permanent, and the impact of masturbation on the physical issues leading to ED start to get better in as little as seven days.

It might take a longer while to fix any mental or emotional issues that rose from masturbating too much, and even longer to address what it did to your relationship…but the sooner you stop, the sooner that process begins.

The Bottom Line: Quit jerking off excessively. Especially to hard-core, video pornography.

It’s bad for your penis, your brain, and your relationships.

3: Get Better Sleep to Reverse ED

Here’s something your mom and grandma told you, that it took science until recently to figure out. If you don’t sleep enough, it’s bad for you.

Even though our culture glorifies men who give up sleep to work harder and “crush it,” or simply to show how tough and dedicated they are…

We’re finding more evidence each day to suggest men who get too little shut eye lose the focus and productivity they need to do well at the jobs they’re trying to “crush.”

And it’s even worse for your sexual health. If you’re not getting a solid 7-8 hours a night, you’re doing all kinds of damage to your erectile and hormonal health (source):

Insufficient sleep lowers your testosterone production. Less testosterone = lower libido. Lower libido = less desire and less ability to get hard.

Insufficient sleep harms your cardiovascular health in a variety of ways. As I mentioned in the first entry on this list, poor cardiovascular health means poor erectile health because you rely on blood flow to get hard.

Insufficient sleep can lead to depression, which can cause physical, emotional, and relationship problems with your sexual health.

Insufficient sleep reduces your nitric oxide production. Nitric oxide (NO) is one of the most important chemical components of your body’s process for becoming aroused.

Insufficient sleep increases your stress, and reduces your ability to handle what stress you experience. Stress is the most common emotional and lifestyle factor that can create ED and other sexual health issues.

Finally, a 2009 study found that 70 percent of men with sleep apnea (which causes profound sleep loss) also had erectile dysfunction (source).

This study didn’t look into why either symptom happened, or whether a single cause was at the root of both, but clearly establishes a connection between ED and low quality sleep.

The Bottom Line: Get 7-8 hours of sleep per night or your penis will go on strike.

4: Fix Metabolic Issues to Reverse ED

Your “metabolism” refers to a variety of processes that surround how your body interacts with, takes in, and burns energy.

It’s a big, complex topic.

So it should come as no surprise that some aspects of it also impact your sexual health. The three most important of these are:

High Blood Pressure means restricted blood flow and stress on your body’s tissues. Both of these are so linked to erectile health that 30% of men with high blood pressure also experience ED symptoms (source).

Blood pressure medications aren’t a good long-term fix for this. In fact, Viagra started development as a blood pressure treatment.

Instead, aim for natural methods of lowering your blood pressure

Drink beet juice, eat celery, take an olive leaf extract supplement, and/or drink coconut water. All of these natural fixes have been proven to reduce or eliminate high blood pressure.

High Blood Sugar stresses several aspects of your endocrine system, and can lead to diabetes. Whether it’s full-blown or just incipient, this harms both your blood flow (see above), and your nerve function (which leads to a less sensitive penis).

You can reduce your blood sugar in two ways: eat less refined sugar, and exercise more to burn off the sugar you do eat.

I recommend both. You can also add magnesium, chromium, berberine, and omega 3 fatty acids to your supplement regimen. They all help minimize blood sugar.

Body Fat Around the Waist. Being overweight in general isn’t great for your erectile health, but abdominal fat is especially bad. The presence of abdominal fat stimulates your body’s production of aromatase.

Aromatase is a liver enzyme with the main function of turning your testosterone into estrogen. I don’t need to re-explain why less testosterone might be bad for your erectile health.

Worse, it’s a vicious cycle.

One thing estrogen does is push your body to pack on extra fat, especially around the abdomen and chest. That extra fat means more aromatase, which means more estrogen, which means more fat, which means…

The solution here is to lose weight, which will have the nice side benefit of reducing blood sugar levels as well.

But weight loss is a long-term project…

In the short term, a few supplements that can inhibit your aromatase production include ashwagandha, caffeine, white button mushroom extract, grape seed extract, mangosteen..

And Nettle Root.  (scroll down to the headline….Nettle is a Natural Aromatase Inhibitor).

You’ll also notice that all three of the items in this section can be addressed by getting moderate exercise two or three times a week.

That’s not just good for your sexual health, either. It’s a good idea no matter your age or fitness level.

The Bottom Line: Get off the couch, gents. Your body needs you to fix your blood pressure, blood sugar, and body weight.

5: Address Substance Abuse to Reverse ED

I shouldn’t have to tell you how bad illegal drugs are for your health, wellness, mental state, and relationships.

If you have a problem with something like cocaine, meth, or heroin…seek help immediately. I mean, right now. This article will still be here when you’re clean.

But illegal drugs aren’t the only ones that can cause erectile dysfunction. Three commonly used, and commonly prescribed, drugs are solidly proven to wreak havoc with your erections.

Alcohol in the short term can cause your “little buddy” to pass out before you do. While you’re drunk, the communication between nerve cells and your brain slows and sometimes misses entirely. That includes communication for arousal and erection.

In the long term, alcohol can permanently damage nerve cells and harm circulation, both of which directly impact your sexual health. There’s also solid research suggesting that alcohol consumption reduces testosterone and increases estrogen in men.

Opiates and opiate dependency are also related to erectile dysfunction, to the point that 50-60 percent of men seeking treatment for opiate addiction also experience ED.

Research is still progressing as to why, but some early findings point to opioids reducing testosterone, and messing up the pathways between your hypothalamus, your pituitary gland, and your gonads.

SSRIs — Selective Serotonin Reuptake Inhibitors — are to mental pain what opiates are to physical pain. They interrupt your ability to feel the pain, and have been deeply overprescribed over the last several years..

SSRIs reduce dopamine production, delay or prevent ejaculation, increase refractory periods, limit penis sensitivity, and reduce your libido.

Who would have guessed drugs designed to reduce emotional range might have the side effect of limiting sexual activity?

The Bottom Line: Stay off drugs, kids. Even legal ones. To the extent you can, even some your doctor tells you to take.

One Last Thing…

If you want to reverse ED, you want to stay away from ED drugs. That may sound counterintuitive, but here’s the thing.

Big Pharma isn’t interested in curing ED, because if they cure it, they can’t sell you more Viagra or Cialis.

ED pills temporarily relieve the symptoms of erectile dysfunction, but they do nothing to reverse the factors causing it.

Worse, physicians like Dr. Geoff Hackett of Good Hope Hospital in the UK warn that ED treatable by medication is a warning sign for heart problems.

Taking ED drugs to beat the symptom may leave a serious, life-threatening health issue undiagnosed and untreated.

Bottom line: use the techniques above to address the causes of ED. Don’t just cover up the symptoms with Viagra or Cialis. One method can reverse your problems. The other only prolongs them.

How to Reverse ED Conclusion:

Look at it this way…

Erectile dysfunction is a legitimate condition and sometimes the condition can’t be cured right away.  But that doesn’t mean you can’t make rapid improvement.

Women are generally weaker than men — just like men with ED generally have weaker erections than men without.

But a woman who power lifts every day and plays rugby for fun will be stronger than a man who hasn’t been to the gym since high school and spends all his time playing video games.

It’s all about how you respond to the situation…

If you address the issues that apply to you above, your erections will be much stronger than if you do nothing at all.

And if you stay the course, you may actually find yourself using the word Cured in the not too distant future.

That said…

If you ever find yourself up against a roadblock, you can always use a little herbal support to take things to the next level.

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Pine Pollen Testosterone

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A Powerful Erection Booster

Pine Pollen, Testosterone…pine-pollen-testosterone

Two words you need to remember if your bedroom performance could use a lift.

Because pine pollen does one thing incredibly well…

It facilitates increased testosterone production inside the testicles…without causing testicular atrophy.

And this is a Huge point.

You can almost look at this stuff as the plant version of anabolic steroids…without all the negative B.S.

But that’s not all it can do…

Because pine pollen is basically tree sperm. Acrobatic semen that gets blown into the wind with the hope….

That it will land on a female ovary (blossom) and inseminate it.

This is how pine tree babies are made.

And like the sperm of any species, this tree shoots out some potent material…that for some Strange Reason….

Human males respond really well to.

Pine Pollen also impacts sex hormone binding globulin, nitric oxide production AND estrogen balance in human males.

So this stuff works on hormones and on erections.

But it’s important that you cycle this herb so you don’t develop tolerance to it.

You can read more about cycling here.

Now here’s more on this subject from Spencer…

Pine Pollen Testosterone Part 2:

There are several natural ways to help you get it up bigger and better than ever…

Remedies that have been passed down for thousands of years and remedies that have just been discovered.

Pine pollen is one of those hundred year remedies. Whether you’re struggling with erectile dysfunction, or you just want some harder wood, pine pollen can really help you get going.

Here’s how…


Pine Pollen Effects & Benefits

Pine pollen is a supplement derived from (obviously) the pollen of pine trees, usually the Masson pine, the Chinese oil pine, or the Scots Pine.

Aside from helping ED, it has wide range of benefits that will make you healthier, and more sexually fit (source)

First, pine pollen is full of vitamins, minerals, and amino acids, which collectively work to help your body function at a higher level.

Second, pine pollen has loads of sterols, which are naturally occurring plant steroids.

In pine pollen, sterols work to benefit your total health in a range of ways:

• Brassinolide improves liver function
• Castasterone is a strong antiviral
• Gibberellins help regulate prostate size

In addition, pine pollen has been used in China for thousands of years as an anti-inflammatory treatment, as a way to clean up free radicals, and to slow the aging process.

However, its major use remains for its tremendous (and natural) improvement of your morning wood.

Pine Pollen And Erectile Dysfunction

Pine pollen will help increase your testosterone levels through its role as an androgen. But testosterone isn’t the only way that it can help you get (and keep) a good erection.

Pine pollen also works to improve your erections in two other ways: with arginine, and through superoxide dismutase, or SOD.

I’ve talked about arginine and ED before, but the core idea is that arginine is required to produce nitric oxide, which in turn is needed to get blood flowing to your penis and then to hold it there.

Pine pollen, arginine, and ED

Pine pollen contains natural arginine that your body will put to use to build stronger erections. Arginine is good for your sperm too, improving sperm motility, general fertility, and cranking up sperm production.

The result is a better erection with more (and better) swimmers.

Superoxide dismutase (SOD)

SOD is an enzyme that acts in your body to break down free radicals. When it comes to ED, oxidative stress (having too many free radicals in your body) has been linked to age related ED (source).

The problem is that free radicals effect the metabolic pathways that lead to NO production and the natural release of cGMP.

Basically, when you’ve got too many free radicals running around, your ability to achieve an erection will diminish.

SOD is an enzyme that can specifically target the type of free radicals that cause the most problems (superoxides), and can alleviate the symptoms quickly and easily.

At the end of the day, pine pollen helps you get hard by both increasing how much NO you have in your system, and decreasing the number of roadblocks you have to go through to get your erection.

This dual action is why it’s so effective, and why it’s been used for hundreds of years to treat ED.

And that’s all without testosterone…

Pine Pollen Testosterone Part 3:

Pine pollen is one of nature’s greatest sources of testosterone and other androgens, particularly phytoandrogens.

Phytoandrogens are testosterone for plants. But they work for us too.

What makes pine pollen so unique is that instead of simply providing you a boost of testosterone, it actually promotes your bodies ability to build its own…..

With a combination of the adaptogenic effects of phytoandrogens and the fact that sterols promote testosterone production by binding to the receptors in your testicles.

Other androgens in pine pollen include DHEA, androsterone…and androstenedione, a weaker androgen that’s an intermediary step in the production of testosterone.

By boosting your entire androgen system, pine pollen helps facilitate the production and absorption of testosterone and other male hormones, which in turn improve your libido.

So what sort of improvements? Big ones…

First, low fertility is associated with low levels of testosterone production in your testes.

Because pine pollen improves your ecosystem for testosterone production, rather than just shooting you full of testosterone, it’s actually going to increase your ability to produce sperm at a higher rate, leading to better fertility over time.

It’s like teaching a man to fish, rather than buying him a sandwich.

Second, by increasing how much testosterone is in your body, you’re going to increase how much dihydrotestosterone (DHT) you have as well.

This is the main regulator of both cGMP and nitric oxide, which means that you’ll find it easier to get hard when you want.

And finally, this pine pollen testosterone connection will help you reverse the effects of andropause and keep your hormones in balance. This is key to having a successful sex life.

Update – Pine Pollen & Inflammation

We’re updating this article because a new group of studies shows another important way pine pollen can help solve your erectile dysfunction issues.

Turns out, pine pollen acts as a powerful natural anti inflammatory.

Why does this matter?

Because inflammation is one of the primary drivers behind erectile dysfunction in humans.

That may seem to make little sense, since an erection could be described as “inflammation of the junk.”

But it’s much more complex than that, and matters more than you might think.

Science has known for a while that some causes of inflammation also cause ED.

Examples include smoking, drinking and eating inflammatory foods like highly refined carbohydrates and low quality omega 6 fats.

Correlation and causation aren’t the same thing, but when two things are closely linked such as inflammation and ED, there’s a good chance fixing one can fix the other.

Adding more weight to this argument, we now know beyond a shadow of a doubt that inflammation can exacerbate a variety of circulatory problems.

And as you probably already know, healthy circulation is vital if you want to avoid erectile dysfunction…

So anything that reduces or prevents inflammation will lead to better circulation and will also reduce or prevent ED.

For example, even inflammation of the gums can cause ED, according to work by researchers at the Luzhou Medical College in China (source).

In this study, scientists found a direct and proportional correlation between gum inflammation in rodents and reduced erectile function.

Bottom line: if pine pollen can reduce inflammation, it can help with your erectile dysfunction.

Now, let’s take a look at a few more pine pollen studies…

Kyunghee University, Seoul, Korea.

Back in 2007, a team of researchers in the Nutrition department investigated what pine pollen extract could do with inflammation and pain in mice.

This study first induced inflammation of the paw and ear. They gave the mice an extract of pine pollen, in doses of 100 or 200 mg per kilogram of body weight.

The pine pollen extract significantly reduced inflammation of the paw and ear, and did so more with the higher dosage than with the lower dosage.

This study also tested the impact of pine pollen on pain threshold.

The less said about those methods, the better…but the results led researchers to say the pain and inflammation reduction qualities of pine pollen were similar to that of a full dose of aspirin (source).

Fast-forward one year…

Following up on their research, the same team looked at the chemical processes behind their results with experiments on tissues gathered in-vitro from mouse specimens.

The science on this one is pretty technical…

It includes stuff along the lines of “antioxidant activity increased with the addition of PPE to the linoleic acid emulsion.

Pine pollen extract was also found to inhibit significantly the amount of malondialdehyde and protein carbonyls, etc…”

Engaging our scientist-to-english dictionary…

The study applied pine pollen extract to love cells to test its properties as an antioxidant and antiinflammatory.

What they found was that pine pollen reduced inflammation and oxidation by directly interfering with the biochemical process that causes inflammation in rodents and in humans.

In 2009, the team was ready to attempt a treatment protocol…

They treated mice who were somehow given arthritis with pine pollen extract and monitored whether the pine pollen reduced joint inflammation in the rodents.

After 49 days, arthritis-related inflammation was “markedly reduced” in the subjects.

The researchers concluded…

Pine pollen was a potentially effective treatment for chronic inflammatory illnesses.

The bottom line?

If inflammation is contributing to your erectile dysfunction, pine pollen will almost certainly help.

Pine Pollen Side Effects

There are few reported side effects of pine pollen for the vast majority of users.

Unlike manufactured steroids, PP does not cause down regulation of testosterone, nor does it cause testicular shrinkage.

Some people are allergic to pine pollen and (obviously ) should avoid using it.

The best option is to give it a try and see how it goes, starting with a smaller dose the first time if you’re prone to allergies.

Pine Pollen Products

There are a few variations on pine pollen supplements that you can take, but it’s most common forms are either as a tincture or a powder.

Pine Pollen Tincture

A tincture is a liquid extract mixed with alcohol. In this case, it’s basically pine pollen put in a jar with alcohol (or another solution like vinegar) and left for a few weeks.

It’s possible to make your own, but it’s unlikely to be as potent as what you can buy from a reputable source.

Here’s the brand I recommend and use myself.

The benefits of taking pine pollen as a tincture is that you get the full absorption of all the phyto-androgens, including DHEA.

Oftentimes, these are lost in the digestive tract when pine pollen is consumed as a powder. For this reason, and because your body can absorb liquids faster than powders, you get a big hit of testosterone right away.

That’s why tinctures are the recommended product for treating ED for men over 30.

Pine Pollen Powder

Power is the second main form that pine pollen takes. This is simply pollen that’s been collected, dried, and ground up.

If you go the powder route, make sure you know how it’s processed…

Pine pollen exists within a cellulose shell and the only way to crack that shell is to heat it – but if you heat it too much, you’re going to denature the enzymes and make it less effective.

So what you want to look for is a supplier that offers cracked pine pollen powder, who cracks it by heating it very gently for a long time.

These products are typically a bit more expensive, but the extra cost is worth it.

Pine Pollen Dosage

To treat erectile dysfunction with pine pollen powder, a dose of three tablespoons (standard dose is one tablespoon) dissolved in 8oz of water and you should see results as soon as the next morning.

If you are a man over 30 though, I’d say opt for the tincture extract. Because it’s more concentrated, it’s a good option to kickstart your testosterone production. I’d recommend 30 drops, which is the amount found if you fill the dropper to the top.


Pine pollen is a great source of testosterone and other androgens that are quite effective at keeping your morning wood and your daytime erections alive.

By improving your natural ability to produce testosterone, as well as catalysing the various metabolic processes that you need to get hard, it’s truly one of nature’s greatest hidden treasures.

Whether you opt for the hefty dose of a tincture, or the control of a powder, pine pollen is sure to make you feel good and turn your sex life around.

Pine Pollen Testosterone – References:



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Why Eat Healthy?

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That really is the question proposed in the article what are the benefits of eating healthy published by Medical News Today. There were several benefits of a healthy diet including weight loss, a reduced risk of cancer and diabetes management. All of those seem like good reasons to stick to a healthy diet. But for

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