Low Dose Quercetin as a Geroprotector in Mice

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Quercetin is used in combination with dasatinib as a senolytic treatment capable of selectively destroying senescent cells, but quercetin used by itself is not meaningfully senolytic. Researchers here show that long term low dosage with quercetin modestly slows aspects of aging in mice, however, without extending life span. They evaluate a number of potential mechanisms, including possible reductions of the inflammatory signaling secreted by senescent cells. All in all an interesting paper, particularly for the investigation of effects on retrotransposons. I expect that most interventions shown to slow aging will turn out have some impact on retrotransposon activity, but that has yet to be investigated rigorously.


Quercetin (Que) is a natural bioflavonoid. Que (50 mg/kg) in combination with dasatinib (5 mg/kg) (abbreviated as D + Q) has been shown to effectively eliminate senescent cells via induction of apoptosis, thus alleviating senescence-related phenotypes and improving physical function and lifespan in mice. We recently identified Que as a geroprotective agent that counteracts accelerated and natural aging of human mesenchymal stem cells (hMSCs) at a concentration of as low as 100 nmol/L, which is 100 times lower than the concentration of Que (10 μmol/L) previously used in combination with dasatinib.

To explore the geroprotective effect of low-dose Que in rodents, we evaluated the in vivo effect of long-term low-dose Que administration under physiological-aging condition. Que was given to 14-month-old C57BL/6J male mice by weekly oral gavage at a concentration of 0.125 mg/kg body weight, which is 80-400 times lower than that of the previously tested D + Q (10-50 mg/kg body weight) regimens. After eight months of treatment, Que-treated mice showed decreased hair loss with normal food intake, body weight, blood glucose and bone mineral density. Compared to control mice, mice subjected to Que treatment showed markedly improved exercise endurance. However, the lifespan was not prolonged by low-dose Que treatment observed up to the age of 31 months. Taken together, these data indicate that long-term low-dose Que administration alone sufficiently improves multiple aspects of healthspan, but not lifespan, in mice.

To investigate how Que improved healthspan in mice, we collected 11 different kinds of tissues from 10-week young male mice (Y-Ctrl) and control (O-Veh) and low-dose Que-treated 22-month old male mice (O-Que). Given that exercise endurance and diastolic function were improved by Que, we particularly examined the changes in skeletal muscles (SKM), white adipose tissues (WAT), brown adipose tissues (BAT) and hearts. Upon Que treatment, the arrangement of muscle fibers became more regular and compact with less fibrosis and senescence. In WAT, the increases in adipocyte size and senescence-associated β-galactosidase (SA-β-Gal)-positive area during aging were both alleviated upon Que treatment.

We previously observed that Que alleviates hMSC senescence in part through the restoration of heterochromatin architecture in prematurely and physiologically aging hMSCs. Constitutive heterochromatins are predominantly comprised of repetitive elements (REs), including retrotransposable elements (RTEs). The expression of RTEs is repressed via epigenetic regulation under normal conditions but is elevated during physiological aging, eliciting active transposition. Accordingly, mobilization of RTEs is likely to be a key contributor to tissue aging innate immune responseand cell degeneration. To test whether Que treatment may also repress activation of RTEs in a mouse in vivo model, we compared the transcriptional levels of RTEs in multiple tissues of Y-Ctrl, O-Veh, and O-Que mice. Consistently, most RTEs were transcriptionally upregulated in the SKM and BAT of old mice compared to those of young mice and were repressed by Que treatment.

In senescent cells, the activation of RTEs leads to genome instability, which subsequently promotes senescence-associated secretory phenotype (SASP). Consistently, the inflammatory cytokine IL-6 was increased in old mice compared to young mice and Que antagonized the increase of IL-6 in both hMSCs and old mouse SKM and BAT. Thus, our data suggest that Que may block SASP through the axis of heterochromatin-RTEs-innate immune response pathway. Our data provide important evidence supporting the role of low-dose Que in safeguarding genomic stability (i.e. inhibition of retrotransposition), which at least in part contributes to its geroprotective activity in rodents.

Link: https://doi.org/10.1007/s13238-019-0646-8

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Quercetin Coated Nanoparticles Shown to be Senolytic in Cell Cultures

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Quercetin, while used in combination with dasatinib as a senolytic therapy capable of destroying senescent cells, is not meaningfully senolytic on its own. One argument as to why this is the case is that compounds of this class are not very bioavailable – in other words that quercetin, suitably modified, or delivered in a different manner, would be senolytic enough to form a basis for therapy. Researchers here take the approach of coating nanoparticles with quercetin molecules, and find that the resulting particles can selectively kill senescent cells in cell culture, unlike quercetin alone. This is a promising demonstration, particularly if we consider that it might be applied to the much more senolytic flavenoid fisetin, but it is always best to wait for animal data before becoming too excited by any given approach.


Cellular senescence may contribute to aging and age-related diseases and senolytic drugs that selectively kill senescent cells may delay aging and promote healthspan. More recently, several categories of senolytics have been established, namely HSP90 inhibitors, Bcl-2 family inhibitors and natural compounds such as quercetin and fisetin. However, senolytic and senostatic potential of nanoparticles and surface-modified nanoparticles has never been addressed.

In the present study, quercetin surface functionalized Fe3O4 nanoparticles (MNPQ) were synthesized and their senolytic and senostatic activity was evaluated during oxidative stress-induced senescence in human fibroblasts in vitro. MNPQ promoted AMPK activity that was accompanied by non-apoptotic cell death and decreased number of stress-induced senescent cells (senolytic action) and the suppression of senescence-associated proinflammatory response (decreased levels of secreted IL-8 and IFN-β, senostatic action). In summary, we have shown for the first time that MNPQ may be considered as promising candidates for senolytic- and senostatic-based anti-aging therapies.

Link: https://doi.org/10.1016/j.redox.2019.101337

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Maximum Muscle for Better Health and Longevity

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Maximum Muscle for Better Health and Longevity
Marie Spano MS, RD, CSCS, CSSD

Adults who are stronger may live longer, healthier lives. Greater muscle strength means you can do more. Instead of sitting on the sidelines of life, you’ll be in the game. Imagine canoeing, hiking, spending long days at amusement parks and swimming in the ocean through your later years of life. Greater strength can also keep you independent in your older years and therefore in your own home for a longer period of time.

Maintaining Muscle with Movement

The best way to maintain muscle is by using it. If you don’t use it, you lose it. The Centers for Disease Control and Prevention physical activity guidelines for adults suggest doing resistance training 2 or more times per week. If you are finding it tough to fit in any exercise, don’t let these recommendations alarm you. You don’t need fancy equipment to fit exercise in throughout the day. Also, many daily activities can give your muscles a workout.

One of the best ways to get physically and mentally energized is to fit in exercise breaks during the day. Ten minutes of climbing stairs, wall squats, exercise with resistance bands, pushups (on the floor or against a wall) or any other type of exercise will benefit your health. Try resistance training in 10 – 15 minute increments throughout the day. If you work in a dress and heels, carve out time during your lunch break. Or, keep small weights at your desk and do arm curls and tricep kickbacks.

In addition to working out, there are many activities in daily living that can double as resistance training. Using a vacuum, garden tillers or other large equipment can certainly give your body a workout. Moving furniture, lifting boxes and cleaning your car can also support muscle health. The most important thing is to get moving and stay moving. Look for opportunities to add physical activity every day.

Protein for Muscle

In addition to moving, dietary habits matter when it comes to muscle. Protein intake and total daily calories are the two most important considerations. While the general recommendation for protein intake is around 0.8 grams per kilogram of body weight daily, adults who are active need approximately 1.2 – 1.8 grams of protein per kilogram of body weight per day to maximize muscle growth and repair.[i] The amount of protein consumed per meal is also important. Studies have found adults generally need 25 – 30 grams of high-quality protein per meal. Some adults who have more muscle may need more than this per meal or more than 3 meals to meet total daily protein needs.[ii] High-quality protein is easily digestible and contains all essential amino acids (all are needed to maximally stimulate muscle growth). Most animal-based proteins, including dairy, beef, poultry and eggs, contain all the essential amino acids. Soy is one of the only vegetarian protein sources that contains all the essential amino acids and therefore, for maximum muscle growth, other plant proteins need to be combined to make up for any missing essential amino acids.

Related Article:  Pea Protein as a Vegan Protein Powder Option

Many people, especially those who crash diet, will lose muscle when they lose weight. To prevent this, it is important to consume greater amounts of protein to prevent the breakdown of muscle during weight loss. Muscle can be broken down and the amino acids used as a source of energy to make up for a lack of calories. Anyone on a diet may need up to 2.4 grams of protein per kilogram of body weight per day.[iii], [IV]

Why is Muscle Recovery so Important?

Training hard will give you results. However, if you push yourself during training, you may end up tired, sore and with a decrease in strength in the days after you train. Excess muscle soreness can interfere with movement. Your running motion may be off or it may be tough to completely bend or straighten your arm. Soreness, strength loss and changes in movement can get in the way of your workouts. Check out the Life Extension Exercise Enhancement Protocol  for more information on how to help maximize the health and longevity benefits of exercise.

Recovery nutrition refers to what you eat in the hours after you train. Paying attention to recovery nutrition can help you make the most of your training sessions, minimize muscle soreness, restore strength and keep your energy high. Everyone, regardless of their fitness level, should pay attention to recovery nutrition to ensure they get the most from every training session.

As a professional sports dietitian, I find athletes feel much better if they eat or take a protein shake soon after training. They have more energy the next day and they are not as sore. Post-training carbohydrates are used as energy to build and repair muscle and restore glycogen levels – your fuel tank of energy stored in muscle. More glycogen in muscle means improved endurance during your next bout of training.

In addition to carbohydrates, it is important to get a good serving of protein within 2 hours after training. After you train you are breaking down more muscle than you are building. A good amount of protein can flip this to greater muscle building.

Protein Supplements: What to Look For

Protein supplements are great for recovery because they are convenient and offer the amino acids you need. If you are in a rush or don’t feel like eating, a protein supplement can help fill a nutrition gap. Protein supplements can also help you re-hydrate.

Related Article: How Whey Protein Fights Aging

Protein supplements come in powder form, ready to drink (RTD, liquid), gummies and bars. Powder protein supplements are typically the most cost effective. Gummies and bars have a lower protein content per serving than a powder or RTD. However, all are viable options. If you haven’t eaten in 4-5 hours and are about to work out, it is a good idea to consume protein pre-workout. Consuming protein at this time helps ensure you are getting regular servings of protein to up-regulate muscle growth. Otherwise, it is not necessary to consume protein before a workout. Instead, consume protein from food or a supplement within 2 hours after training.

In addition to zoning in on protein and carbohydrate after training, antioxidant compounds called anthocyanins can support recovery. Return to our blog tomorrow to read the research behind how antioxidants from tart cherries can support muscle recovery!

About the Author: Marie A. Spano, MS, RD, CSCS, CSSD,is a nutrition communications expert and one of the country’s leading sports nutritionists. She enjoys the challenge of communicating scientific information in an approachable, understandable format to a variety of audiences. Spano has appeared on NBC, ABC, Fox and CBS affiliates, and authored hundreds of magazine articles and trade publication articles, written book chapters, marketing materials and web copy on a variety of topics ranging from novel food ingredients to preventing sarcopenia. She is the lead author of the college textbook Nutrition for Sport, Exercise and Health and co-editor of the NSCA’s Guide to Exercise and Sport Nutrition (Human Kinetics Publishers). A three-sport collegiate athlete, Spano earned her master’s in nutrition from the University of Georgia and her bachelor’s degree in exercise and sports science from the University of North Carolina, Greensboro (UNCG). Spano is a member of the National Strength and Conditioning Association (NSCA) and the Academy of Nutrition and Dietetics (AND). http://www.mariespano.com/

References:

[i] Phillips SM1, Van Loon LJ. Dietary protein for athletes: from requirements to optimum adaptation. J Sports Sci 2011;29 Suppl 1:S29-38.

[ii] Lonnie M, Hooker E, Brunstrom JM, Corfe BM, Green MA, Watson AW, Williams EA, Stevenson EJ, Penson S, Johnstone AM. Protein for Life: Review of Optimal Protein Intake, Sustainable Dietary Sources and the Effect on Appetite in Ageing Adults. Nutrients 2018; 10(3): 360.

[iii] Phillips SM. A Brief Review of Higher Dietary Protein Diets in Weight Loss: A Focus on Athletes. Sports Med 2014; 44(Suppl 2): 149–153.

[iv] Pasiakos SM, Cao JJ, Margolis LM, Sauter ER, Whigham LD, McClung JP, Rood JC, Carbone JW, Combs GF Jr, Young AJ. Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: a randomized controlled trial. FASEB J 2013;27(9):3837-47.

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A Perspective on Longevity Biotech Investment from James Peyer of Kronos BioVentures

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James Peyer, formerly of Apollo Ventures and now at the larger Kronos BioVentures, has a range of interesting views on the new and growing longevity biotechnology industry. Apollo Ventures was one of the earlier longevity-focused funds to emerge from the comparatively small community of scientists, patient advocates, and investors enthusiastic to accelerate progress towards the treatment of aging as a medical condition. The presentation here was given earlier this year at the Ending Age-Related Diseases conference organized by the Life Extension Advocacy Foundation.

In the matter of creating new medical therapies, there is a huge, well known, gaping chasm between academia and industry. Neither side of the chasm is all that good at the process of transferring promising projects from proof of principle in the laboratory to clinical development in a biotechnology company. Worthy projects languish and die because of this incapacity. This is a major issue for our community now that rejuvenation research, after the SENS model of repairing the underlying damage that causes aging, has come to the point at which projects are far enough along to begin commercial development. James Peyer’s efforts represent one of the possible solutions to this challenge: a much more active venture funding community, one in which the investors do not wait around for entrepreneurs to show up at the door, but are specialists in the science themselves, capable of creating companies to carry forward promising research projects.

James Peyer | Biotechnology Investment


Hello, everyone. Many of you may know me from Apollo Ventures. Now, from a month or two ago forward, I will be affiliated with Kronos BioVentures. The switch here is not one of particular substance; we had to change an organization, I wanted to do a lot more investments, and do much bigger investments. So we went from Apollo to his grandfather Kronos, when we changed the name.

I am speaking towards the end of this event, so if I were to come up here and talk to you about the aging space or even the investment considerations, it would be a lot of repetition from other presentations today. So I wanted to do something slightly different with my time today, and it is going to be a little data-heavy, and a little bit different. We’re going to do three things, that I will call a perspective, a prospect, and an approach. I’ll cover, number one, some ways of talking about aging in this longevity biotech space, that I think a lot of us aren’t necessarily thinking about, or it isn’t the first thing that I usually hear. Then I want to talk about the present situation in biotech venture capital, particularly biopharmaceutical VCs. Then I want to talk about my favorite strategy in this space, both for biopharma VCs and for the longevity biotech space, which is VC-partnered venture building. Which is more than half of what I do – that’s my hammer that I’m striking every likely-looking nail with, and then building a VC-backed company around it.

To dive in I have just about a dozen slides which I think are interesting perspectives on the aging space. I’m going to talk here about demographic, economic, and human health problems. I’m not going to touch on social solutions, because I think we’re all here for the medical solutions. My first slide: it is important to remember that modern demographics present a new problem. This longevity issue that we’re facing is quite a new thing to come to the forefront of people’s minds. We are only now entering the fourth stage of what is called the demographic transition – as we go from a situation which is the natural state of humans, where we have very high birth rates and very high death rates. We then evolve through this population explosion that happens in stage two, towards a more stable population distribute in which birth rates and death rates are relatively low. We’re just entering that stage.

So this issue of having old people around in large numbers, dying of diseases like cancer and Alzheimer’s, and having complications like type 2 diabetes and osteoporosis, is a relatively new situation. One hundred years ago, the three leading causes of death for humanity were influenza, tuberculosis, and pneumonia. Today they are dementias, cancer, and cardiovascular diseases. This is the key thing in understanding the “why now” of the longevity space – that we are in the midst of this demographic transition.

To illustrate this a bit more, here are some projections based on the UN numbers. My favorite statistic in looking at demography is the old-age dependency ratio. This is the number of people 65 and older divided by the number of people younger than 65, the working age adults 15-64. What you can see, both in the developed world and the undeveloped world, is that these ratios are rising dramatically over this century. In 1950 we’re at about 12% in the developed world, and we’re going to be almost 50% by the end of the century. That is a huge change.

The important thing to remember here is that as we get all of these older people in our society, our society is not set up to support these people. So we come up with this economic problem, which is that, already, in the middle of this graph, the middle of this demographic shift, in the developed world we already have a crisis of underfunded pension obligations as we make commitments to people who can’t work in old age – because they are going to get sick. This right now, according to Citibank, is about $78 trillion worldwide in unfunded or underfunded pension liabilities. I think you can make a credible case that they only way to prevent this incredible number from getting even bigger, and causing even more social and economic calamity, is by making people live longer and healthier, so that they can contribute more to society, even in the late stage of the demographic transition.

Next, from a human health perspective, many of you have seen variants of this graph, but I just wanted to do it with many more diseases, showing the incredible association of aging with all of the leading causes of death. This shows a normalized occurrence rate, so every year you have a chance of getting a heart attack, or getting cancer. So if you plot the chances of getting cancer this year, versus the highest chance you’ll ever have in your life, what you’ll see – for all of these diseases – is that the older you are, the higher your risk becomes. That is true for cardiovascular disease, Alzheimer’s, Parkinson’s, diabetes, and kidney disease.

Moving right along, one of the things that we don’t talk enough about in the aging space, but is critically important to understand why we think the technologies that the longevity biotech world is developing will be so powerful, is the issue of multimorbidity. That is basically having more than one chronic condition at once that you have to deal with. What you can see here is that as people get older, as you move towards 75, by that age about 41% of all people have at least two chronic conditions – and many of them have more. Then that number goes up and up and up as you get older. So people aren’t just dealing with their atherosclerosis, they are dealing with diabetes, with COPD, with senility, all at the same time. For that reason this great analysis, done by Dana Goldman and colleagues in 2013, shows that because there are all of these risks that come up together, if you just reduce risk and prevent one type of disease, let’s say reducing cancer risk, or reducing heart disease risk, you get almost no extension in healthy life span. Almost none. Here 75 years is the base case, and 76 years is what you get just by reducing the risk of one type of disease. If, however, you reduce risk of all the age-related diseases together by a smaller amount, only then do you see a huge jump in life span.

So this was a little tour of some perspectives that I like when thinking about this space. The last one I’m going to leave you with before we jump to the more technical financing part is this graph of life expectancy in the US over time. These are the UN projections for average life expectancy over the next century. When I went back far enough in the data, these are really clear projections forward of the trend from about 1970, it is almost a straight line. But I think that what we are at the cusp of in in the development of technology around longevity biotech is much less like this period from 1970 to 2020, where we were just starting to understand what the diseases of aging were actually caused by, what molecular characteristics they have, and how to approach them. I think that our new situation is going to be much more like the period from 1910 to 1950, when we were actually conquering many of the infectious diseases that were the leading causes of death at that time. We spend perhaps 50 to 100 years characterizing the germ theory of disease and then developing tools like vaccines and antibiotics, and as a result saw a massive upswing in average life span. So my projection here is that as we conquer the diseases of aging we’ll see a slope as new drugs come out that will be more similar to the earlier era in which we were conquering infectious diseases than in the later era when we were not making that much medical progress in treating aging.

Now on to the second part of the presentation. I’m going to show you six slides that will encapsulate what I think of biopharma VC space. We’re all in this universe of the startup ecosystem in biotech, and I think that, especially as this little niche industry that hasn’t launched many approved drugs, it is important to analyze what this bigger industry actually is, how it works, and what kind of success rates we should be expecting. I want to start with an overview of what the biopharma space is. These are companies that make drugs that go through clinical trials. That is most of what we do in the longevity space. There are a couple of interesting trends that have been happening in the biopharma space generally. The first is that the phase at which acquisitions are happening – most companies will ultimately get acquired by a pharmaceutical company, which will then run the latest stage trials and sell the drug – and those acquisitions have been happening earlier and earlier. You can see in the white line here, these are preclinical and phase I stage companies. Since 2013, the numbers of acquisitions of commercial and phase III stage companies have been going down.

So companies have been acquired earlier, but even though they are being acquired earlier, they are being acquired for larger amounts with less time spend in development of those companies. As an investor, these three facts are really exciting. It means that you are making more money, faster, and you have to do less work to get there. On the one hand that means this is a great time to be investing in biotech. On the other hand, it also makes investors worried.

Here is the second graph; most new drugs today come from biotech startups. This is a massive shift from what the world looked like twenty years ago. Twenty years ago you had the pharma companies that would either in-license stuff from academia, or they would do their own research and development to find drugs and approve those drugs. In 2017, 75% of all of the approved drugs came from biotech startups. Many of them were acquired and ultimately did the final trials with Big Pharma, but that is also a hugely defining factor. That means that the vehicle of choice for getting an approved drug is a biopharma startup.

Thirdly: drugs that come from startups do better in the clinic than drugs from Big Pharma. There is something that I find absolutely magical about the ability to take a very dedicated team of founder and founding scientist and throw them into a problem and say, alright, you guys need to get this thing to work. Your company, and everything that comes with it, many times reputation, many times validation of the scientific theory, all rides on getting this question right and answering this question in the right way. That pays off in the long term, because when drugs ultimately launch, it is almost twice as good for a drug to start in a biotech startup and be licensed to Big Pharma when compared to internal development in Big Pharma.

Fourth: total amounts of VC funding per round have been going up enormously in the last couple of years, particularly in 2017 and 2018 – I have the medians and the means graphed here. This chart shows average size per round, and you can see that in 2018 that series A and series B rounds for average biotech companies were around $30 million. That is a lot of money. Seed rounds, however, are staying relatively small – $2-3 million is the normal there.

Fifth: IPO valuations have been going up and up and up for preclinical and phase I stage assets, but not for phase III. Before I get to my last piece, I want to close on this overview of where we are in the biotech investment space. You can draw two conclusions as you look at these five pieces of data. The first conclusion is that this is absolutely the time to be doing a biotech startup in innovative drug development. The second conclusion is that this looks a lot like a bubble. If you look at the macroeconomic situation, starting from where a lot of my data starts, from 2011 until now, the stock market has been riding high, we’ve been in this expansionary economy. So a lot of investors who are thinking about, today, where I want to commit my money for a drug development program, they have to think about how is this market going to look three, four, five, ten years in the future. There are some worrying signs, for us, that we have to be taking this risk of a bubble in biotech very seriously.

One of the signs that is most apt is this graph. For those of you who don’t know, 2018 was the biggest year ever for IPOs in biotech companies. There were over 60 IPOs. However, something a little bit disturbing came along with these IPOs. On this graph, each company is a bar, and the size of the bar indicates what percentage change their stock has had between their IPO in 2018 and the end of 2018. You can see that more than half of them declined – and a lot of them declined by a lot, in less than a year. What this means to me is that the public markets are really, really harsh on these early stage biotech companies. Because there is an exuberance, many companies are jumping into the public markets without having to show any more data. Now that they are subject to public scrutiny, by people who aren’t trading on the potential of the company, but instead on what has the company done, they get hammered. This makes private investors, long term investors to fund clinical development that much more important. Potentially more important than it has ever been. It also means that investment going forward in the next five to six years is probably going to have to be more disciplined. I don’t think that this IPO window, with high valuations and freely available funds, is going to last.

That leads me to five quick conclusions about the biotech VC space. Number one, avoid exuberance as much as possible. Number two, focus on seed investments, getting in really early, as round sizes are not increasing there. Getting in early and following things through, the timing and the amounts make a lot sense. Number three, don’t plan for the IPO ecosystem to continue the way it has been. Number four, only exit when you have a clear value story, and you are confident that you can actually back away from the project. Don’t just throw it out into the world and see how it goes. Number five, and this is important, there are some cautionary things here, but I think that, overall, the trend that we’ve been seeing in the biotech ecosystem will continue.

I didn’t spent time on the data here, but the main reason that a lot of this boom has been so exaggerated is that Big Pharma research and development is changing fundamentally. Resources are going away from the Big Pharma companies doing research and development into biotech startups. That space that is being created, it isn’t being filled fast enough. So even though there are a lot of resources going into it, and there is a lot of excitement, Big Pharma companies still desperately need their pipelines to be filled – and filled with good drugs. So this space will continue to grow, as this trend continues in moving to this more efficient method of creating drugs in biotech startup companies.

My last piece that I want to do, very quickly, is just a little bit on my approach to how to play in this world, and how I’ve been working with scientists and entrepreneurs to do this. This is a venture-led company building process, where I think that there are five key things that a company needs to do in order to pull together their story and become a real biotech company. Number one, you identify exceptional research, and in our case it is longevity research. Number two, you partner with the people who know the science intimately, and never do a company without the scientists that know what they’re talking about. Work with the scientists that know the science, because when you run into trouble, and you will always run into trouble when doing basic research, they are the only ones who have run into the same thing ten times before, and know the answers to what is going on. It will slow down a company enormously if you don’t have those guys.

Number three, biotech is a bit unique compared to the tech world in how different the different phases of a company are as it progresses through its value chain. The guy who knows how to get toxicology studies done and the guy who knows how to correctly do a phase III clinical trial and the guy who knows how to successfully sell a drug on the marketplace are completely different from the guy who knows how to make a basic discovery in fruit flies. So having a team that comes in at the appropriate time to lead this process at the right time for that company is a characteristic of the best biotech companies that I know. One of the reasons that I want to focus on this VC-led or this company building model, and why I think it works so well, is that you have people in the board of directors or who helped to create the company that exist somehow behind the operational team, and the operational team can be led by a different person, whoever is needed the most for that phase of the company. But the overall mission and vision and science of the company can be supported by the founders all the way through, which is a model I really love.

Number four, you have to design your key value creating experiments, like what is the killer experiment, without this there is nothing. Then do that experiment and fail fast if you are going to fail. Then number five, biotech development is very expensive. You need to have a path to $20 million or $30 million rounds to do clinical trials. If you don’t think that you’ll be able to raise that money, then you need to have a partner on board early on who you think can.

Next slide, and I’m not going to spend a lot of time on this, in company building we do things in three phases. My favorite way of looking at building companies is in a hypothesis-led way. Whether you are an entrepreneur or a venture investor this, I think, should be the start: come up with a hypothesis. Then explore, validate the hypothesis, get the people on board, and then create the company. Then my last slide; it is easy to focus in on Silicon Valley and Boston as the two largest biotech hubs in the world. I think that doing so leaves so much on the table. Great basic research can be found everywhere in the world. There are fantastic institutions in Europe, in Southeast Asia, in the center of the United States that are underexplored. So a big part of what I do at Kronos is to look around at where that great research is done, and then move forward wherever it is, with a team that can actually accelerate it.

So anyway, that is a bit of my perspective on the longevity biotech space. Thank you for your attention; hopefully some of you found this useful information.

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The Collapse of Proteostasis in Later Stages of Aging

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Proteostasis is the name given to successful maintenance of youthful levels of proteins and minimal protein damage in cells. With age, the molecular damage of aging leads to changes in expression of proteins and dysfunction in cellular maintenance processes. The result is ever more damaged proteins and altered cellular behavior. Some of those behavioral changes are compensatory, some cause further disruption to cell and tissue function. Loss of proteostasis is a hallmark of aging, but it isn’t a root cause of aging. It is a downstream consequence of forms of damage that change cell behavior and impede the operation of cellular maintenance via autophagy or the ubiquitin-proteasome system.


In higher organisms, cells age and die by natural processes. What are the molecular mechanisms that drive it? It has been difficult to disentangle causes from effects because aging impacts most cellular biomolecules. Oxidative damage is known to play a key role. Much of what is known about cellular aging comes from “bottom-up” experiments, by perturbing a few genes at a time – by knockouts, knock-ins, or point mutations, or by gene-to-gene comparisons using sequence databases. Our interest here is in the “top-down” question of the aging mechanism, which we take to be a more system-wide failure in the cell. Any single gene cannot reverse aging or abolish life span limits. Oxidative damage is indiscriminate and nonspecific in which class of biomolecule it hits or its spatial location in the cell. We take the mechanism of aging and longevity to be more about a general and stochastic destruction than a pinpoint action.

One view is that aging results from declining protein quality-control systems involved in protein synthesis, degradation, and chaperoning that normally protect the proteins in the cell’s proteome. Central to proteostasis, the decline in protein quality control is implicated in more than 50 diseases of abnormal protein deposition (proteinopathies), for which the principal risk factor is advancing age, probably because cell regulation and protein production and disposal becomes increasingly compromised with age. Proteostasis is a natural culprit in aging because it is a front line of response to stress and because proteins are the primary repairers of the cell and sustainers of the genome.

Here, we model how proteostasis – i.e., the folding, chaperoning, and maintenance of protein function -ncollapses with age from slowed translation and cumulative oxidative damage. Irreparably damaged proteins accumulate with age, increasingly distracting the chaperones from folding the healthy proteins the cell needs. The tipping point to death occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage. The model agrees with experiments in the worm Caenorhabditis elegans that show the following: Life span shortens nonlinearly with increased temperature or added oxidant concentration, and life span increases in mutants having more chaperones or proteasomes. It predicts observed increases in cellular oxidative damage with age and provides a mechanism for the Gompertz-like rise in mortality observed in humans and other organisms. Overall, the model shows how the instability of proteins sets the rate at which damage accumulates with age and upends a cell’s normal proteostasis balance.

Link: https://doi.org/10.1073/pnas.1906592116

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A Role for Acetylcholine in Sarcopenia

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It has been suggested that some fraction of sarcopenia, an age-related loss of muscle mass and strength leading to frailty, is caused by dysfunction of neuromuscular junctions, the points of integration between muscle and nervous system. This is as opposed to the more straightforward loss of stem cell function, leading to a lesser capacity for muscle growth and tissue maintenance. Acetylcholine has a prominent role in the function of neuromuscular junctions, and on this basis researchers here demonstrate that reduced levels of acetylcholine lead to both improvement in the structure of neuromuscular junctions and a slowing of the progression of sarcopenia in aged mice.


In addition to driving contraction of skeletal muscles, acetylcholine (ACh) acts as an anti-synaptogenic agent at neuromuscular junctions (NMJs). Previous studies suggest that aging is accompanied by increases in cholinergic activity at the NMJ, which may play a role in neuromuscular degeneration. In this study, we hypothesized that moderately and chronically reducing ACh could attenuate the deleterious effects of aging on NMJs and skeletal muscles. To test this hypothesis, we analyzed NMJs and muscle fibers from heterozygous transgenic mice with reduced expression of the vesicular ACh transporter (VAChT), VKDHet mice, which present with approximately 30% less synaptic ACh compared to control mice.

Because ACh is constitutively decreased in VKDHet, we first analyzed developing NMJs and muscle fibers. We found no obvious morphological or molecular differences between NMJs and muscle fibers of VKDHet and control mice during development. In contrast, we found that moderately reducing ACh has various effects on adult NMJs and muscle fibers. VKDHet mice have significantly larger NMJs and muscle fibers compared to age-matched control mice. They also present with reduced expression of the pro-atrophy gene, Foxo1, and have more satellite cells in skeletal muscles. These molecular and cellular features may partially explain the increased size of NMJs and muscle fibers. Thus, moderately reducing ACh may be a therapeutic strategy to prevent the loss of skeletal muscle mass that occurs with advancing age.

Link: https://doi.org/10.3389/fnagi.2019.00262

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Evidence for Human Cell Division Rates to Decrease with Age

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We humans exhibit a peak cancer incidence in old age, around the early 80s, after which cancer rates decline from that peak. If aging is the continual accumulation of damage, then why do we observe this pattern of cancer incidence with age rather than a continual increase over time? It does not occur in mice, after all. Researchers here provide evidence for the explanation to involve reduced rates of cell division in later life, which may be one of many evolutionary adaptations connected to the unusual longevity of our species when compared with other similarly sized mammals, and particularly other primates. If there is less cellular replication, then potentially cancerous mutations will occur less frequently and spread less rapidly.

The divergence of human longevity from other primates is thought to have its origin in our culture and intelligence. Once it became possible for older members of society to contribute meaningfully to the fitness of their descendants, then there is selection pressure for longer life spans; this is expressed in the the Grandmother Hypothesis. Since human culture and longevity are comparatively recent developments in evolutionary terms, we might expect to find comparatively simple aging-related differences between humans and other mammals in the behavior of cells and tissues in the aged environment. Changes in stem cell behavior, or changes in cell replication rates in a damaged environment, for example: alterations that reduce the risk of death by cancer at the cost of a drawn out decline into loss of function.

Novel Study Documents Marked Slowdown of Cell Division Rates in Old Age


In a novel study comparing healthy cells from people in their 20s with cells from people in their 80s, researchers say they have documented that cell division rates appear to consistently and markedly slow down in humans at older ages. The researchers say the findings may help explain why cancer – long considered a disease of aging, with incidence highest among people over age 65 – has been found to decelerate in occurrence at the extreme end of human life. The findings, they say, also provide clues about cell biology that might eventually lead to a better understanding of cancer.

Cancer is spurred by an accumulation of genetic mutations caused by mistakes cells make when copying DNA during cell division. Research in the last several decades assumed that such mutations accumulate over time at a steady rate. However, when researchers reanalyzed old data in dozens of published papers, they found that mutations accumulate more slowly in old age. That analysis led researchers to suspect that cell division rates slow down markedly in old age, giving cells fewer chances to accumulate DNA mistakes.

To test this hypothesis, the team analyzed cell replication rates in samples of various healthy tissues collected during biopsies and other medical procedures from more than 300 patients in their 20s and in their 80s. Their findings showed that cell division rates slowed by about 40% in colon tissue samples collected from patients in their 80s compared with those in their 20s. Similarly, in samples of esophageal tissue, the division rate slowed by about 25% in the elderly compared with the younger patients. In the duodenum, at the beginning of the small intestine, the rate slowed by 26% in the elderly, and in posterior ethmoid sinonasal tissue, found near the nose, the rate slowed by 83% in the elderly.

When researchers performed a similar analysis of cell replication using tissue from young and old lab mice, they found no significant differences in the division rate – a considerable distinction between mice and humans that could make it more difficult to use aging mouse data as a proxy for aging humans.

Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence


A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all four tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice.

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Fermented Dairy Lowers Heart Disease

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Nearly 610,000 people die each year from heart disease, which accounts for 25% of all deaths in the U.S.1 Each year 735,000 have a heart attack; in this group, it was the first cardiac event for 525,000 of them. According to the American Heart Association, the annual cost of cardiovascular disease and stroke was estimated at $351.2 billion in 2014-2015.2

The American Heart Association also reports that 116.4 million Americans have high blood pressure and that someone dies of a stroke every 3.7 minutes.3 Individuals who have high blood pressure or diabetes, as well as those who are physically inactive, overweight or obese have the highest risk.4

According to the Centers for Disease Control and Prevention, 10% of the U.S. population has diabetes and up to 95% of those have Type 2 diabetes.5 Symptoms may develop over several years and may be difficult to spot: As your pancreas produces insulin, the cells do not respond, which increases blood glucose levels.

Although many who are diagnosed are 45 years and older, as the rates of childhood obesity have risen, so has the rate of Type 2 diabetes in young people. Of the top 10 leading causes of death in the U.S.,6 heart disease and diabetes are the leading or contributing factors in five. In the past few decades scientists have focused on how to reduce the risk of acquiring these conditions.

Inverse Link Between Fermented Dairy and Heart Disease

Two recent studies have demonstrated an inverse relationship between the daily amount of fermented dairy consumed and the development of heart disease. A similar link was found in studies analyzing the dietary effects in men7 and women.8

The studies were undertaken by two different teams. The first was completed by researchers at the University of Eastern Finland and published in mid-2018 in the British Journal of Nutrition.9 Researchers asked whether fermented dairy products offered protective effects for cardiovascular health.

They compared fermented and unfermented dairy products in 1,981 men enrolled in the Kuopio Ischemic Heart Disease Risk Factor Study; none had coronary heart disease upon enrollment. The researchers recorded fatal and nonfatal heart events and dietary intake, including fermented and unfermented dairy products, during a mean follow-up of 20 years.

They found those who had the highest intake of fermented products had a 27% lower risk of heart disease; this was contrasted by those who had the highest intake of unfermented dairy products and suffered a 52% higher risk of heart disease. In this study, milk was the unfermented product most often consumed. The researchers used a measurement of 0.9 liters (3.8 cups) or more each day as a high amount.10

Authors of a recent study published in The Journal of Nutrition11 also analyzed the relationship between fermented dairy products and cardiovascular disease, this time in an Australian population. Using the Australian Longitudinal Study on Women’s Health, researchers enrolled 7,633 women without heart disease and followed them for 15 years, using surveys to ascertain dietary intake and self-reported outcomes.

They found a high intake of yogurt and fermented dairy products was associated with a lower risk of heart disease. They acknowledged that in previous studies, this inverse relationship with risk was not detected. However, in the past, the outcome that was measured was mortality, as opposed to the current study in which a new onset of diagnosed cardiovascular disease was the measured outcome.

It’s also worth noting that the types of unfermented dairy counted in the survey included various milk products such as full cream milk, reduced fat milk, skim milk, soy milk and flavored milk.

Link With Type 2 Diabetes Not Found in Australian Study

In the Australian study evaluating the effect of fermented and unfermented dairy products on women’s health, researchers also looked at Type 2 diabetes. Of the women who did not have diabetes at the start of the study, 9.2% — 701 — developed the disease during the 15-year follow-up period.

The researchers found that women who ate the highest amount of yogurt had the lowest adjusted odds of Type 2 diabetes compared to those who ate the least. However, once the data were adjusted for other dietary variables, along with total energy intake, the relationship was no longer significant.12

Those who ate the most yogurt consumed an average of 114 grams per day. To put this in perspective, individual containers of Yoplait yogurt contain 6 ounces or 170 grams.13 The label indicates one serving of this brand is 3.5 ounces (100 grams).

However, as reported by a study team from Harvard University,14 “… a higher intake of yogurt is associated with a reduced risk of Type 2 diabetes.” The team followed 194,458 men and women over 3,984,203 person years and found that yogurt did not increase the risk of Type 2 diabetes but, rather, eating one serving a day reduced the risk of the disease.

Differences in Raw and Pasteurized Milk

Although the authors of the Australian study found that women who drank the greatest amount of unfermented milk products had a higher association with heart disease, as I already mentioned, the data were based on women who regularly drank several types of milk, including full fat, low-fat and soy. To that end, I feel that it’s important to note that data from the Prospective Urban Rural Epidemiology (PURE) study, published in The Lancet15 reveal vastly different results.

The PURE study was a large, multinational investigation with individuals from 21 countries across five continents. Researchers compared the consumption of whole fat dairy products to rates of cardiovascular disease and mortality. They gathered records over the course of 15 years and found that when individuals only ate full fat dairy, they had a reduced risk of death and major heart disease events.

However, not all full-fat dairy products are created equally. U.S. government agencies such as the U.S. Food and Drug Administration and the U.S. Department of Agriculture argue that drinking unpasteurized raw milk may be a ticket to disease and death.

But the reason milk products are pasteurized and heated to kill bacteria is because, without pasteurization, that bacteria often find their way into the milk as a result of the dreadful conditions cows in which concentrated animal feeding operations (CAFOs) live and produce milk. The overwhelming majority of milk in the U.S. is produced on CAFOs and is pasteurized.

Cows are supposed to eat and digest grass, but in CAFOs they are fed genetically-engineered grains and soy products, and often deprived of sunlight. They also are exposed to each other’s excrement, in which they stand until workers clean the area. Even though the cows go through a sanitizing wash before they’re milked, the animals are given antibiotics to ward off and counter infections, and the milk is pasteurized to kill the bacteria.

However, dead bacterial proteins remain in the milk and are not removed. As your body digests these foreign proteins, it may produce an allergic response. On the other hand, cows raised on grass produce high-quality milk and whey protein, reducing the allergic effect some people experience.

Pasteurization destroys many of the valuable nutrients found in cow’s milk, some of which are important for digestion of the product, resulting in digestive issues you may experience when drinking milk or eating cheese. For more information about using and purchasing raw milk, see my past article, “Why is Raw Milk Illegal?

Yogurt Offers More Benefits

Results from both the Australian and Finnish studies confirmed that fermented dairy products may protect you against heart disease. These products include kefir and yogurt where live bacteria are present. One study scientist, Jyrki Virtanen, adjunct professor of nutritional epidemiology at the University of Eastern Finland, told Newsweek:16

“Our findings and those from other studies suggest that fermented dairy products may have health benefits compared to non-fermented dairy. Therefore, it might be a good idea to use more fermented dairy such as yogurt, kefir, quark and sour milk. Some of the beneficial effects of fermented dairy products may relate to their impact on the gut microbiota.”

Most yogurt sold in the U.S. is sugar-sweetened and fruit-flavored, but in other countries yogurt is paired with lemon, garlic, cumin and olive oil. It may be used as a base for sauces and vegetables, and it’s becoming more popular to find Greek yogurt dips and salad dressings.

If you’re eating yogurt to optimize your gut flora, then you may want to steer clear of commercial yogurt brands that have more in common with candy than health food. Seek out organic yogurt made from 100% grass fed or pastured whole milk, rather than low-fat or skim. You could also start making yogurt at home.

As I’ve written before, yogurt is a top food for fighting inflammation, much of which may occur as yogurt affects gut bacteria. By eating homemade yogurt, you’re able to control the ingredients, boost its health properties and flavor the product to your liking.

It’s easy to add fresh berries or a squirt of your favorite juice once the product is ready to eat. Compared to pasteurized varieties, yogurt made with raw milk is thicker, creamier and nutritionally superior.

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How Leucine in Whey Helps Prevent Muscle Loss

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The loss of muscle mass that occurs with age is known as sarcopenia, the most obvious cause of which is inactivity. Sarcopenia can progress at a rate of approximately 0.8% skeletal muscle loss per year from the fifth decade in adult life.1 It has an estimated prevalence of 10% in adults older than 60 years,2 rising to more than 50% in adults older than 80 years.3,4

Your diet also plays a role, as your muscles need sufficient amounts of protein to stay viable, as does your ability to digest and absorb protein. As noted in a 2011 paper5 in the American Journal of Nutrition:

“Sarcopenia has been attributed to a diminished muscle protein synthetic response to food intake. Differences in digestion and absorption kinetics of dietary protein, its amino acid composition, or both have been suggested to modulate postprandial muscle protein accretion.”

In other words, while you need protein to build and maintain muscle, some protein is more easily digested and absorbed than others, so eating the right kind of protein can make a difference in your risk for sarcopenia.

Whey protein, a byproduct of cheese production, has long been acknowledged as an excellent source of protein. In this 2011 study, in which whey protein was compared to casein and casein hydrolysate, whey protein was found to stimulate muscle protein accretion (and hence stave off sarcopenia) the best — in part due to its higher leucine content.

The type of exercise you do can also make a big difference. I now believe blood flow restriction (BFR) training is one of the best ways to prevent sarcopenia. Taken together, leucine supplementation through whey and BFR can go a long way toward protecting your muscles as you age.

Leucine Regulates Protein Turnover in Muscle

One of the reasons why leucine is so important for the prevention of sarcopenia is because it helps regulate the turnover of protein in your muscle. According to a 1975 paper6 in The Journal of Clinical Investigation, leucine may also “play a pivotal role in the protein-sparing effect of amino acids.” As explained in a more recent study,7 published in 2017:

“Protein ingestion produces a strong anabolic stimulus that elevates muscle protein synthesis. The ability of a serving of protein to stimulate muscle protein synthesis (MPS) is dependent on absorption and blood kinetics of amino acids, amount of protein ingested, and the amino acid composition of the protein source.

Only the essential amino acids (EAA), especially leucine, initiate an immediate increase in MPS. Being a rapidly digested protein with a high leucine content, whey has been shown to stimulate MPS more than equal amounts of casein and soy in the first hours after exercise …

At the molecular level the mechanistic target of rapamycin complex 1 (mTORC1) and its substrates … are believed to largely be responsible for the protein synthetic response to resistance exercise and protein intake, with resistance exercise potentiating the effect of protein ingestion.”

In other words, the most effective way to optimize muscle building is to use a combination of resistance training followed by a protein meal, with leucine-rich whey being one of the most efficient.

Ori Hofmekler, author of “Unlock Your Muscle Gene: Trigger the Biological Mechanisms That Transform Your Body and Extend Your Life,” is an expert on how to use food to build muscle and improve your health, and we have previously discussed the profound benefits of whey protein for muscle building in particular.

It is important to understand, though, that simply taking leucine is likely to be ineffective, as demonstrated by a recent Harvard study.8 In it, men over the age of 65 with a daily intake of 0.8 grams of protein per kilo per day were compared to men receiving 1.3 grams of protein per kilo per day. They found the higher protein group did not increase lean body mass, muscle strength or physical function, most likely because they were not exercising.

The Importance of Glutathione for Prevention of Sarcopenia

Whey protein also contains another really important health component: glutathione. While many whole foods contain glutathione or its precursors, organic grass fed whey protein is one of the richest sources of this “master antioxidant.”

Glutathione is found in every cell of your body. It protects your cells from free radical damage, and is especially important for liver health. It differs from other antioxidants in that its intracellular and has the unique ability to optimize the activity of all other antioxidants.

It plays a crucial role in detoxification, and protects your cells form the damaging effects of radiation, chemicals and environmental pollutants. It’s also an essential factor in energy utilization and healthy immune function, and glutathione deficiency has been linked to a wide range of health problems, including Alzheimer’s9 and Parkinson’s,10 heart disease,11 autoimmune diseases,12 inflammatory conditions13 and mitochondrial dysfunction.14

Glutathione is thought to play an important role in sarcopenia specifically, as patients with sarcopenia tend to have higher levels of oxidative stress.15 As noted in the 2012 review,16 “Rationale for Antioxidant Supplementation in Sarcopenia:”

“Sarcopenia is an age-related clinical condition characterized by the progressive loss of motor units and wasting of muscle fibers resulting in decreased muscle function.

The molecular mechanisms leading to sarcopenia are not completely identified, but the increased oxidative damage occurring in muscle cells during the course of aging represents one of the most accepted underlying pathways.

In fact, skeletal muscle is a highly oxygenated tissue and the generation of reactive oxygen species is particularly enhanced in both contracting and at rest conditions.

It has been suggested that oral antioxidant supplementation may contribute at reducing indices of oxidative stress both in animal and human models by reinforcing the natural endogenous defenses …

Antioxidants are substances able to inhibit the rate of oxidation. Mainly, antioxidant enzymes (e.g., catalase, superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase) work to maintain a state of balance preventing the transformation of ROS and to convert them into more stable molecules (like water and molecular oxygen).”

Prevent Muscle Wasting With BFR

While high-quality protein intake is important, to effectively build and maintain muscle you also need strength training. Unfortunately, many elderly individuals shy away from resistance training for fear of injury.

BFR is ideal in such situations, as the amount of weight you use is so low that your risk for injury is minimal. For a more detailed discussion of BFR and how it’d done, see “Build Muscle Faster, Safer and Easier With BFR Training.”

Please understand, though, that this article is a mere teaser. I will be providing a comprehensive report within the next month about how to do BFR, its history and instructional videos. I have been working on this for nearly six months now and it is nearly ready.

In the meantime it is important to know that BRF involves exercising your muscles while partially restricting arterial inflow and fully restricting venous outflow in either both proximal arms or legs.17 Venous flow restriction is achieved by using thin elastic bands on the extremity being exercised.

By restricting the venous blood flow, you create a relatively hypoxic (low oxygen) environment in the exercising muscle, which in turn triggers a number of physiological benefits, including the production of hormones such as growth hormone and IGF-1, commonly referred to as “the fitness hormones.”18 

It also increases vascular endothelial growth factor (VEGF), which acts as “fertilizer” for growing more blood vessels and improving their lining (endothelium).

I believe BRF is one of the best strategies available to address the epidemic of sarcopenia,19 and for most people who are not competitive athletes it may be the only form of resistance training they need.

It’s important to realize that sarcopenia is not just cosmetic, and it’s not just about frailty. Your muscle tissue, which makes up about half of your body’s tissues, is a metabolic organ, an endocrine organ. Your muscle tissue makes cytokines and myokines, and is a sink for glucose.

Insulin resistance and Type 2 diabetes accelerate sarcopenia, and research shows glucose fluctuations are independently associated with this condition. As noted in one 2019 study,20 “glucose fluctuations were significantly associated with a low muscle mass, low grip strength, and slow walking speed.”

BFR Effectively Counteracts Sarcopenia

The effectiveness of BFR for the prevention and reversal of muscle wasting is directly addressed in an April 2019 study21 in the Journal of Cachexia, Sarcopenia and Muscle:

“Muscle wasting leads to significant decrements in muscle strength, cardiorespiratory, and functional capacity, which increase mortality rates. As a consequence, different interventions have been tested to minimize muscle wasting.

In this regard, blood flow restriction (BFR) has been used as a novel therapeutic approach to mitigate the burden associated with muscle waste conditions.

Evidence has shown that BFR per se can counteract muscle wasting during immobilization or bed rest. Moreover, BFR has also been applied while performing low intensity resistance and endurance exercises and produced increases in muscle strength and mass.

Endurance training with BFR has also been proved to increase cardiorespiratory fitness. Thus, frail patients can benefit from exercising with BFR due to the lower cardiovascular and join stress compared with traditional high intensity exercises.

Therefore, low intensity resistance and endurance training combined with BFR may be considered as a novel and attractive intervention to counteract muscle wasting and to decrease the burden associated with this condition.”

Leucine Dosage and Timing

As mentioned, leucine is a branched-chain amino acid that serves multiple functions, one of which is signaling the mTOR mechanism, which causes protein to be created and builds your muscle. However, according to Hofmekler, for optimal results you need far higher amounts of leucine than the recommended daily allowance.

The reason for this is because most of the leucine is used up as an energy substrate or building block rather than an anabolic agent. The typical requirement for leucine to maintain body protein is 1 to 3 grams daily. However, to optimize its anabolic pathway, Hofmekler insists (and research shows22) you need somewhere between 8 to 16 grams of leucine per day, in divided doses.23,24

Getting that amount of leucine from your regular diet could be pretty difficult. For example, 4.6 eggs will provide you with 2.5 grams of leucine,25 which means you’d have to eat nearly 15 eggs to reach the 8-gram minimum.

For most, that simply wouldn’t be possible and would overdose you on protein (105 grams of protein from the eggs alone). High-quality whey, on the other hand, contains about 10% leucine (10 grams of leucine per 100 grams of protein).26 So, 80 grams of whey protein will give you 8 grams of leucine.

Ideally you’ll want to consume the whey about 30 to 60 minutes before exercise, and again about an hour after your workout. This will help increase both fat burning and muscle building.

A 2010 study27 found that consuming whey protein (20 grams of protein per serving) 30 minutes before resistance training boosts your body’s metabolism for as much as 24 hours after your workout.

Other Health Benefits of Whey Protein

Whey protein has undergone extensive study, revealing an impressive array of benefits over and above its ability to support healthy muscle growth. For example, studies show whey consumption may also:

  • Help lower blood pressure and improve vascular function if you’re overweight and/or have high blood pressure28
  • Support normal blood sugar levels and boost insulin sensitivity in Type 2 diabetics29
  • Reduce inflammation,30 including inflammation associated with inflammatory bowel disease (IBD)31 — In the case of IBD, researchers have suggested its protective actions may be the due to its ability to stimulate intestinal mucin synthesis and modify the composition of the gut microbiome
  • Help normalize your weight — Not only is whey protein very filling, thereby reducing hunger pangs32,33,34 it also boosts metabolism35 (allowing you to burn more calories) and helps maintain lean muscle mass while shedding excess fat stores36

Guidelines for Buying High-Quality Whey

Whey derived from cheese manufacturing that uses raw grass fed milk is the highest quality whey you can possibly find today. One of the most important components of the whey is glycomacropeptides (GMP), which have amazing immuno components that are critically important for your gut flora.

However, only whey produced from raw milk cheese contains GMP. Other varieties do not. Whey isolate is a clearly inferior form of whey that should be avoided, because once the fat has been removed, you lose some of the most important components of its immunological properties. So, to ensure you’re getting a high-quality product, make sure the whey you’re buying is:

Organic (no hormones or genetically engineered ingredients)

Grass fed

Made from unpasteurized (raw) milk

Cold processed (as heat destroys whey’s fragile molecular structure)

Minimally processed

Full of rich, creamy flavor

Water soluble

Sweetened naturally, not artificially

Highly digestible — Look for medium chain fatty acids (MCTs), not long chain fatty acids

Sarcopenia Is Not an Inevitable Outcome of Aging

While muscle loss occurs with age, it’s not an inevitable outcome — provided you take proactive measures. To summarize, the way you prevent it is by regularly engaging in some form of resistance training, and BFR has many advantages that makes it an ideal choice.

This is especially true for those who are older, frail or struggling with a condition that makes regular strength training difficult or potentially dangerous. In addition to that, you’ll want to make sure you’re getting enough high-quality protein.

Organic grass fed whey protein is ideal, as it provides high amounts of both leucine and glutathione, both of which are important for muscle growth and maintenance.

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Melanocytes are the Only Epidermal Cells to Show Signs of Senescence with Aging

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Lingering senescent cells arise in every tissue, and their presence is a cause of aging. These errant cells secrete a potent mix of molecules that rouse the immune system to chronic inflammation, degrade tissue structure, and change the behavior of surrounding cells for the worse. The more senescent cells, the worse the effects. Researchers are beginning to look more closely at cellular senescence in aging skin, and the results from the study noted here are particularly interesting. That melanocytes are the only skin cell type to show the canonical signs of senescence is unexpected.

Nonetheless, the negative effects of senescence still exist in this case, and reinforce the expectation that senolytic drugs that reach the epidermis sufficiently well will be capable of reversing skin aging to some degree, just as they have been shown to reverse measures of aging in other organs. Given the present state of knowledge, I expect the benefits of senolytic therapies on skin to be minimal until later life. The skin aging that occurs between 20 and 50 is probably not driven to any great degree by senescent cells, as senescent cell burden most likely scales with age in a similar manner to cancer risk. There will no doubt be clinical trials in the years ahead, and firm numbers where today there are only expectations, but skin aging isn’t all that high on the priority list for most of the companies and research groups working in the field.


Over time, cells in the body can be damaged by external exposures, like ultraviolet radiation from the sun, or internal ones like oxidative stress. On the skin this appears as wrinkles, dryness, or age spots. In the skin, changes occur so the outermost layer called the epidermis gets less nourishment, becomes thinner and is easier to breach. To understand this process on a cellular level, researchers began looking at different cell populations in skin to see if any cell type was associated with skin damage more so than another.

The team initially thought that one type of cell that is abundant in skin and divides often, called keratinocytes, would drive senescence. However they report that melanocytes, the cells which produce the pigment responsible for skin color, fit the senescence profile and released pro-inflammatory factors that could affect surrounding cells and induce skin aging. “Melanocytes divide very little throughout our life and constitute 5-10% of the cells in the basal layer of the epidermis. They showed a variety of molecular markers of cellular senescence in the aging skin. We found that melanocytes became senescent without telomere shortening, which is not surprising since they hardly divide. But melanocytes showed DNA damage specifically at telomere regions irrespectively of their length due to oxidative stress.”

To confirm that melanocytes were really the driver of skin aging, the team built a 3D human epidermis in the lab, and found that melanocytes alone could induce several features of skin aging in the model. They also reported that the effect of the senescent melanocytes could be moderated by treating the model with the senolytic drug ABT-737 or by the mitochondrially targeted antioxidant MitoQ that protects mitochondria.

Link: https://discoverysedge.mayo.edu/2019/10/21/researchers-identify-cells-that-drive-human-skin-aging/

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