Researchers identify molecule with anti-aging effects on vascular system, study finds

[Todd Allen]

The following article and study was posted by Al in his CR Updates thread.  I find it amusing that the focus is on caloric restriction and fasting and the desire to find an easier way to stimulate this pathway.  β-hydroxybutyrate is strongly upregulated merely by restricting carbohydrates.  I've been doing it for 2 years, not hard at all.  And I've had tremendous improvement in bio-markers of cardio-vascular health such as blood pressure, resting pulse and post-exercise pulse recovery.

----

Researchers identify molecule with anti-aging effects on vascular system, study finds
September 10, 2018 
by Latina Emerson
https://medicalxpress.com/news/2018-09-molecule-anti-aging-effects-vascular.html
β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.
Han YM, Bedarida T, Ding Y, Somba BK, Lu Q, Wang Q, Song P, Zou MH.
Mol Cell. 2018 Aug 28. pii: S1097-2765(18)30605-1. doi: 10.1016/j.molcel.2018.07.036. [Epub ahead of print]
PMID: 30197300
https://sci-hub.tw/10.1016/j.molcel.2018.07.036
Abstract
β-hydroxybutyrate (β-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether β-HB alters the senescence pathway in vascular cells remains unknown. Here we report that β-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of β-HB. β-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of β-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that β-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

[mccoy]

Todd, I too was surprised by that article, as if the researchers didn't know that there is a whole new branch of literature on ketogenic diets, where the main marker for ketosis is β-hydroxybutyrate  itself.

The logical extension of that article would be that ketogenic diets are favourable to longevity. 

It is a tough diet to follow though. Almost no carbs, little protein (unless you ingest exogenous ketones). Huge amounts of fats, which gets nauseating. Also, not all people tolerate an high amounts of saturated fats (multiple references from Dr Attia's podcasts).

More, there is no blue zones where a keto diet is followed. The Inuit, often cited as the perfect example of a keto diet (although not longeve at all), do not produce ketones!

So, still it's sort of an unknown territory. 

 

 

[Todd Allen]

14 hours ago, mccoy said:

It is a tough diet to follow though. Almost no carbs, little protein (unless you ingest exogenous ketones). Huge amounts of fats, which gets nauseating. Also, not all people tolerate an high amounts of saturated fats (multiple references from Dr Attia's podcasts).

The version used for medical conditions such as epilepsy where it is important to continuously maintain a very high level of ketones is tough.  Lately, I'm sustaining a moderate level of ketosis,  roughly 0.5 mmol/l with about 50 g net carbs and 100 g protein daily which I find easy.   Some who are more athletic can do it at 100 g net carbs daily.  And being in a low level of ketosis makes fasting fairly easy and ketone levels come up quick in a fast.

[ADPeters89]

Ketosis is difficult.

Being Keto adapted is much easier. Pretty sure that is what you are doing Todd, assuming there is some substantial difference.

That's similar to what I do, but I'm cool with pushing 100g Carbohydrate. Protein is probably around 75g as well.

[Genny]

On 9/12/2018 at 3:31 AM, mccoy said:

Todd, I too was surprised by that article, as if the researchers didn't know that there is a whole new branch of literature on ketogenic diets, where the main marker for ketosis is β-hydroxybutyrate  itself.

The logical extension of that article would be that ketogenic diets are favourable to longevity. 

It is a tough diet to follow though. Almost no carbs, little protein (unless you ingest exogenous ketones). Huge amounts of fats, which gets nauseating. Also, not all people tolerate an high amounts of saturated fats (multiple references from Dr Attia's podcasts).

More, there is no blue zones where a keto diet is followed. The Inuit, often cited as the perfect example of a keto diet (although not longeve at all), do not produce ketones!

So, still it's sort of an unknown territory. 

 

 

We already know that long-term ketosis causes really intractable glucose insensitivity, along with gradually rising levels of both glucose and insulin in the blood.  There is enough glucose from the glycerol on triglycerides to support this.

We also know that it causes really unfavorable alterations in synapse pruning after a prolonged period of time.  I can't find the study now, but it was really damning (and also explains why the people on really long term ketosis seem to become increasingly unbalanced).

 

[Todd Allen]

14 hours ago, Genny said:

We already know that long-term ketosis causes really intractable glucose insensitivity, along with gradually rising levels of both glucose and insulin in the blood.

Can you provide any references to evidence supporting your statements?

Here are two papers from a recent study with results contradicting your claims, greatly improved insulin resistance as measured by HOMA IR via measurements of both insulin and c-peptide and greatly improved fasting blood sugar and HbA1C (with reduction or elimination of blood sugar lowering medications).  Though maybe you are right blood sugar issues are related to high blood triglycerides as well formulated ketogenic diets have been consistently found to also dramatically lower blood triglycerides. 

Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study

Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study

I can't judge your claim on synaptic pruning since you have provided no evidence for it but there is a lot of published science on the neuro-protective effects of ketogenic diets and beneficial effects on a wide range of neurological conditions such as epilepsy, multiple sclerosis, Huntington's, Parkinson's, Alzheimer's, ALS, traumatic brain injury, cerebral ischemia and peripheral neuropathy.  Here's a paper that discusses some of these with many additional references.

Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases

[Clinton]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609489/

After reading the article I linked and what Dr.Peter Attia presents, there is some very strong evidence that KD increases Healthspan significantly (not sure about Kraft Dinner though).

However people doing CRON or even Time Restricted Feeding should have similar or higher ketone levels - so already getting these health benefits.

[mccoy]

Some aspects of the NIH study would suggest that the beneficial effecgts of a KD in rats is correlated to the dietary restrictio inherent in those. The control group, as far as I understood, is fed ad-libitum, so there is no isocaloric state:

Quote

Level of energy intake and prevention of weight gain may be particularly important for positive lifespan effects with a KD, and the results of the present study suggest that longevity is increased when a feeding strategy is followed that mitigates weight gain in adult mice.

Apparently, the KD group was fed an hypocaloric diet, which is the same as traditional CR, barring the different macronutrients ratios.

ttwo more differences, one negative (glucose intolerance) the other positive (lesser weight loss) of KD:

 

Quote

The KD, however, also showed several differences from CR. Unlike CR, the KD mice in the present work were glucose intolerant compared to controls, in contrast with previous reports of enhanced glucose tolerance in ad libitum fed KD (Douris et al., 2015). Additionally, the level of intake of the KD in the present study did not produce the decrease in body weight observed with a CR diet.

But I expect that there was a weight reduction, although not at the same levels of CR. Some outputs of the mTORC cascade are the same in both traditional CR and KD regimens.

My take as related to humans is that KD (traditional KD with low protein) takes to bottom the insulin signal, and that's not always a good thing. IGF-1 is decreased as well, testosterone is bound by higher SHBG so free T drops down, muscular development is thwarted, bodyweight drops. That's good in overweight people who also accept a loss of musculoskeletal tissue.

Bodybuilders also loose weight and muscle mass while on a strict KD, that's why it's prevalently used to shred before contests. The only way to ensure preservation of muscle tissue during KD is use of androgens (and exercise).

I'm aware of people like Dom d'Agostino, who are absolute exceptions, researchers who experiment on themselves and also make anple use of costly exogenous ketones.

Bottom line, the research is still at its inception and there is apparently no definite proof that KD may extend longevity in humans. It may also be dangerous, if lipids and inflammation parameters are not checked. Barring particular conditions, I find it a very unconvenient way to hypothetically gain better longevity and healthspan, unless we desire to practice stoicism and eliminate many foods from our table...Also, if we pursue celibacy that's a good method, considering the absolute crash in free testosterone.

N:B: I tried a KD diet and experienced unwanted weight loss and total loss of libido. Advantage was a more controlled fasting blood glucose. I appreciated though the mental discipline inherent in avoiding simple sugars.

[Saul]

22 minutes ago, mccoy said:

IGF-1 is decreased as well,

Almost all ketogenic diets increase the ratio of protein to carbs.  This increases IGF1, the opposite. 

  -- Saul

[mikeccolella]

Exactly correct Saul and that would indicate some profound, youthful effects, but all the longevity researchers I know would give a big thumbs down long term!

[mccoy]

On 2/19/2019 at 3:20 PM, Saul said:

Almost all ketogenic diets increase the ratio of protein to carbs.  This increases IGF1, the opposite. 

  -- Saul

Are we sure that the ratio governs? I would say the absolute concentration governs, and protein is pretty low in real ketogenic diets (without exogenous ketones). Otherwise the diet would be no more ketogenic.

Insulin also promotes IGF-1 production (indirectly through GH production?). From the wiki voice:

 

Quote

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption.^[10] Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: insulin levels, genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, ethnicity, estrogen status and xenobiotic intake.^[11]

 

[mikeccolella]

https://www.adelaidenow.com.au/news/south-australia/sahmri-research-reveals-why-highprotein-diets-are-bad-for-you/news-story/9277b39a4ad84b5f1ce38b6ddfaf001f?nk=db94ec9b47b2d84b4dda8cee105fbb26-1550338206

 

Al Pater just posted the above. It explains that high protein basically screws up cell metabolism. They use the analogy of speeding increases chance of having an accident. Bottom line according to article is if you want to live a long healthy life go easy on the protein and get it from plants

[mccoy]

That article is maybe too much divulgative, at the expense of scientifical rigour, the real explanation at the level of cellular metabolic signals is missing. And it deals with flies, worms, and in vitro human cells. Not a definitive proof as we probably all concur.

Anyways, as I've been hinting at, we should define what is 'high protein', since the requirements are different for different individuals and vary also in function of the energy input (overall calories ingested).

I agree that 200 grams of protein per day are too much for nearly everyone, probably 150 is too much as well, but what about 100, or 80 ?  An exact quantification is needed for every individual. the present RDA is a cautious point estimate of a random distribution which is probably infuenced by the energy substrate. And it has also collected various criticism from researchers. 

A regimen of caloric restriction most probably requires more protein than caloric abundance in the same individual.

Bottom line, protein requirement (zero nitrogen balance) is very variable and is quantifiable only by trial and error (barring nitrogen balance measurements or similar tests).

[Saul]

Lower your protein.

[Clinton]

Lol.

McCoy, fwiw I consume approx 60g per day now and with about 1600 total calories and 70g of fiber.  None of my aminos are below RDA.

This keeps me both shredded and can still do sets of 6 chin ups and dips with 90lbs on a waist-belt at age 44 - not sure if I can maintain that for long at these calories but we’ll see.

My main sources of protein are some skim milk in my smoothie with walnuts, almonds, and flaxseed twice per day and at lunch with tons of veggies & leafy greens I have a boiled egg with salsa.  Also some lentils

[Taurus Londono]

On 2/19/2019 at 9:20 AM, Saul said:

Almost all ketogenic diets increase the ratio of protein to carbs.  This increases IGF1, the opposite. 

  -- Saul

 

Better call Saul

[mccoy]

20 hours ago, Clinton said:

Lol.

McCoy, fwiw I consume approx 60g per day now and with about 1600 total calories and 70g of fiber.  None of my aminos are below RDA.

This keeps me both shredded and can still do sets of 6 chin ups and dips with 90lbs on a waist-belt at age 44 - not sure if I can maintain that for long at these calories but we’ll see.

My main sources of protein are some skim milk in my smoothie with walnuts, almonds, and flaxseed twice per day and at lunch with tons of veggies & leafy greens I have a boiled egg with salsa.  Also some lentils

Clinton, if by that amount (60 g) you find you preserve muscle mass with no increase, then you are in >=0 nitrogen balance .

If you observe you are loosing muscle mass, you are in negative balance  (hence you need more protein) and conversely if you are gaining muscle then you are definitely in >0 nitrogen balance.

Presently, I'm no more counting protein but following the neurological signals the body provides. I'll eat according to hunger and I'll only eat natural protein without indulgence. No mandatory post workout meal, in my case the anabolic window has a much different timing that the one described in the literature.

[Clinton]

Thanks McCoy- that’s essentially my plan; only ramp up protein if required.

 I simply wanted to point out that I have (I believe) similar body composition goals as yourself and I think (I’m still testing this) that you may be able to have a respectable muscle mass (not huge but approx 22-22.5 BMI) great strength and very little body fat with no more than 1g protein per kg bw

[mccoy]

On 2/23/2019 at 1:38 AM, Clinton said:

Thanks McCoy- that’s essentially my plan; only ramp up protein if required.

 I simply wanted to point out that I have (I believe) similar body composition goals as yourself and I think (I’m still testing this) that you may be able to have a respectable muscle mass (not huge but approx 22-22.5 BMI) great strength and very little body fat with no more than 1g protein per kg bw

Probably so, Clinton, although a severe caloric restriction might push up your protein requirements, but 1 g/kg/d may sure be enough for a functional purpose (again, barring maybe severe CR). 1600 kCal per day might be too little as an energy substrate in an individual who does resistance training, you can only experiment to know. Calistenics might improve because of lesser bodyweight whereas loads lifted may decrease.

Hypertrophy though may be different. In natural bodybuilders it's probably governed mainly by the proper workout and then by the presence of adequate nutrients (whereas we know that strength is not always correlated to hypertrophy).

What I can tell you anecdotally is that in my case, high amounts of proteins have been redundant. I reached 1.6 g/kg/d at 2600 kcal average but I had no real improvements in hypertrophy.

I'm counting protein no more now, I just follow my instinct (governed by various body neurological signals which I want to believe are legit).