Cholesterol paradox

[Sibiriak]

14 hours ago, mccoy said:

but my previous analyses were also done about 2 weeks after an FMD and the comparison shows increased unfavorable values..... 

IIRC,  you lost a bit more weigh on this FMD compared to  the last,  and in any case,  you can't predict exactly how your body is going to react to any given fast.

The main  point, though, as that neither of the cholesterol tests done after your FMDs can be expected to give you an accurate measure of your baseline cholesterol levels.   They both could be widely off.   

This has happened  to me twice.  After my last fast my cholesterol temporarily went up to 200 from my normal average 160.   You really might want to get tested a minimum of two months after your last fast,  just to see if the previous unreliable results were abnormal or not.

 

Edited August 23, 2020 by Sibiriak

[mccoy]

3 hours ago, Sibiriak said:

IIRC,  you lost a bit more weigh on this FMD compared to  the last,  and in any case,  you can't predict exactly how your body is going to react to any given fast.

The main  point, though, as that neither of the cholesterol tests done after your FMDs can be expected to give you an accurate measure of your baseline cholesterol levels.   They both could be widely off.   

This has happened  to me twice.  After my last fast my cholesterol temporarily went up to 200 from my normal average 160.   You really might want to get tested a minimum of two months after your last fast,  just to see if the previous unreliable results were abnormal or not.

MMMmmm, sensible considerations,  I would not have expected such a long timespan of influence from an FMD and by chance all the most recent analyses took place about two weeks after one. Next time around, I'll be more careful about the timing. In one month I might even check my cholesterol at the pharmacy, with a quick test done pricking the finger, maybe less accurate but good for a check.

[Ron Put]

mccoy, fasting may increase plasma cholesterol, as Sibiriac rightly indicates:

Cholesterol Levels Rise After a 24-Hour Fast

 

But as I just did a quick search, I was a bit surprised that a longer-term fast can also increase cholesterol:

Fasting Increases Serum Total Cholesterol, LDL Cholesterol and Apolipoprotein B in Healthy, Nonobese Humans

[Sibiriak]

26 minutes ago, Ron Put said:

Fasting Increases Serum Total Cholesterol, LDL Cholesterol and Apolipoprotein B in Healthy, Nonobese Humans

An interesting detail:

That study involved a pure (mineral) water +vitamins fast ("acute starvation").    However the author cites another study  of a  slightly more moderate fast with different results:

Effect of moderate semi-starvation on plasma lipids (1990)

 

Quote

Abstract

The effect of a daily intake of 200 kcal for 6 days on blood lipid levels of normal and obese subjects was examined. Subjects exhibited a decrease in body weight of 5.9 percent. Plasma glucose levels decreased with no change in insulin levels. FFA and cholesterol did not change significantly with the low caloric intake. Triglyceride and phospholipid concentrations, elevated in obese subjects before the dietary period, decreased significantly with low caloric intake. In contrast no significant changes were observed in triglycerides or phospholipids in normal subjects. Serum uric acid increased during diet in normal but not in obese subjects.

These results show different patterns of changes in plasma lipids in normal and obese subjects on very low caloric intake and raise the possibility of differences in utilization of lipid and protein stores, and may also hint at a role for phospholipids in energy metabolism. Very low calorie and carbohydrate diets may be beneficial for weight reduction in obese subjects without increasing blood lipids.

 

 

I'm not sure how much credence I'd put into that single study, though, considering the fact that,  if I'm not mistaken,  there is quite a bit of evidence that various  weight loss diets increase cholesterol levels.   It's the weight loss --burning fat-- that is seems to be the key factor.   From Ron's cited study:

Quote

The increases in serum cholesterol, LDL and apo B were associated with weight loss.

* * * * *

The average weight loss between d 1 and 8 was 5.5 ± 0.2 kg.

Unfortunately,  the study  does  not do followup testing to see how long it takes cholesterol levels to go down again.

Another interesting point:

Quote

We observed falling serum IGF-I and increasing LDL levels in response to 1 wk of fasting. This is in keeping with the inverse correlation between LDL and IGF-I in nonfasting subjects (Hoogerbrugge et al. 1989). In addition, IGF-I treatment of normal men (Oscarsson et al. 1995) and patients with hypopituitarism (Thorén et al. 1994) decreases cholesterol concentrations. In sum, the negative correlation between serum IGF-I and LDL suggests a causal relationship.

 

 

 

 

[TomBAvoider]

We observed falling serum IGF-I and increasing LDL levels in response to 1 wk of fasting. This is in keeping with the inverse correlation between LDL and IGF-I in nonfasting subjects (Hoogerbrugge et al. 1989). In addition, IGF-I treatment of normal men (Oscarsson et al. 1995) and patients with hypopituitarism (Thorén et al. 1994) decreases cholesterol concentrations. In sum, the negative correlation between serum IGF-I and LDL suggests a causal relationship.

Wow, Sibirak, what a find! This is a real gem! Sibirak I award you the Al Pater prize for Medical Article Digging :) 

I had no idea that IGF-I and LDL were linked like that. I wonder what that means for someone who takes statins. Does that mean that lowering LDL through statins elevates IGF-I? If yes, then I would regard that as a serious negative - I'm not anxious to elevate my IGF-I.

[Sibiriak]

10 hours ago, TomBAvoider said:

I award you the Al Pater prize ..

Wow!  Thanks.  A great honor. But,  with all due respect,  you seem  to  have tendency  to overreact sometimes to a single inconclusive study.

Quote

Does that mean that lowering LDL through statins elevates IGF-I?

That study involved 8 days of "acute starvation"  wherein intense fat burning increased cholesterol levels and reduced IGF-1 levels (presumably temporarily).   The author only states that the data "suggests" a causal relationship between serum IGF-1 and LDL.  

The cited  Hoogerbrugge et al. 1989   study only looked into the relationship between IGF-1 and LDL  levels in women with hypothyroidism:

Quote

A decrease in IGF-I of 65% (P less than 0.005) was seen in hypothyroid patients and this was inversely correlated (r = -0.75; P less than 0.01) with the concentration of LDL cholesterol. Multivariate regression analysis of LDL cholesterol against IGF-I and free T4 showed that IGF-I determines the concentration of LDL cholesterol instead of free T4.

Our data suggest that in hypothyroidism, IGF-I is a determinant of the concentration of LDL cholesterol.

IIRC,   statin use in some patients lowers IGF-1 and may be a cause of muscle problems in some patients.  I could be wrong on that.

Looks like a research project for you:  what do we know about the effect of statins on IGF-1 levels in various types of patients?

Oh, here's a study that shows statins asssociated with increased IGF-1.

Statin administration is associated with higher IGF-1 levels in patients without diabetes mellitus (2018)

Quote

Abstract

Background: Research makes it clear that the IGF-1 level correlates with cardiovascular disease, chronic heart failure, and mortality. Yet, little is known about the effect of statins on IGF-1.

Aims: to evaluate the effect of statin treatment on IGF-1 and its association with a cardiovascular risk.

Material and methods: The study included 115 patients (mean age, 55.8±6.1 years) who either were overweight or had mild obesity (body mass index 28.6±3.8 kg/m2) without diabetes. Group 1 consisted of 70 patients with verified coronary artery disease receiving statin therapy; group 2 included 45 healthy subjects. Coronary angiography and treadmill test were used to diagnose coronary artery disease. Impaired glucose tolerance and total cholesterol, triglycerides, LPHD, LPLD, fibrinogen, and IGF-1 levels were evaluated in all the subjects. Heart chamber geometry was assessed by echocardiography.

Results: The IGF-1 level was significantly higher in group 1 compared to the control group (196 and 167 ng/ml, respectively; р=0.014). Serum levels of IGF-1 were associated with duration of statin therapy (R=0.311; p=0.000), stage of hypertension (R=0.187; p=0.04), fibrinogen (R=0.274; p=0.033), TG (R=0.316; p=0.006), total cholesterol (R=–0.213; p=0.016), LPLD (R=–0.184; p=0.038), smoking (R=0.3; p=0.009), ejection fraction (R=0.298; p=0.041), end-diastolic volume (R=0.422; p=0.036), end-systolic volume (R=0.407; p=0.042), end-diastolic dimension (R=0.27; p=0.014), interventricular septal thickness (R=0.247; p=0.02), and left ventricular posterior wall thickness (R=0.258; p=0.019). Rosuvastatin dose positively correlated with the IGF-1 level (R=0.521; p=0.028).

Conclusions: Statin administration is associated with higher IGF-1 levels in patients without diabetes. High IGF-1 level correlates with the risk factors of coronary artery disease: hypertension, lipid profile, and fibrinogen level and has an adverse effect on chronic heart failure by altering the cardiac remodeling.

But that study deals with diseased patients vs healthy patients,  and it only shows an association,  not causality--  there could be all kinds of confounding factors, reverse causation etc.   Besides,  it's a Russian study.

 

10 hours ago, TomBAvoider said:

I'm not anxious to elevate my IGF-I.

What's your  current IGF-1 level?  

 

 

Edited August 24, 2020 by Sibiriak

[mccoy]

In one of his podcasts, Peter Attia described the changes associated to IGF-1 after one of his 'nothingburger' fasts (7 days keto+7 days water+7 days keto). He reports a drop and then a return to usual values in IGF-1 but I don't remember for how long, I remember his usual values are above the 150s. He might have hinted at lipids levels. I don't remember exactly the podcast though.

[Sibiriak]

A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance and healthspan (2015)

Quote

[...]To evaluate the feasibility and potential impact of a periodic low protein and low calorie FMD in humans, we conducted a pilot clinical trial in generally healthy adults. The components and levels of micro- and macro-nutrients in the human FMD were selected based on their ability to reduce IGF-I, increase IGFBP-1, reduce glucose, increase ketone bodies, and maximize nourishment (Fig. 6) in agreement with the FMD’s effects in mice (Fig. S1).

 

Quote

In the FMD subjects, fasting blood glucose levels were reduced by 11.3 ± 2.3 % (p< 0.001; FMD) and remained 5.9 ± 2.1 % lower than baseline levels after resuming the normal diet following the third FMD cycle (p< 0.05; Fig. 6 B). Serum ketone bodies increased 3.7-fold at the end of the FMD regimen (p< 0.001) and returned to baseline levels following normal food intake (Fig. 6 C).

Circulating IGF-I was reduced by ~24 % by the end of the FMD period (p< 0.001) and remained ~15 % lower after resuming the normal diet (p< 0.01; Fig. 6 D).

IGFBP-1 was increased 1.5-fold at the end of the FMD regimen (p< 0.01) and returned to baseline levels following normal food intake (Fig. 6 E).

 

[TomBAvoider]

I have not measured my IGF-I in a long time, so I actually don't know my current values. Good reminder... something I should do not too long from now. Sibirak, I know you're joking, but I am not particularly dismissive of papers published in Russia (i.e. no more than in the rest of the world - which, to be fair, I'm pretty skeptical of in general) - I'm much more skeptical of any papers coming out of China. Papers out of China I pretty much dismiss, having read so much about absolutely appalling practices there.

[mccoy]

Sibiriak, if I recall it right, beyond the excerpt you quoted, that article doesn't say much about the long-term trend, that is, IGF-1 remained -15% after resuming the normal diet, but for how long? It stands to reason that if the FMD cycles are pretty close to each other, that is one month, the drop may be permanent. Not necessarily so if the cycles are months apart.

In my case, since I measure my blood glucose, I can say that at the end of the FMD it's more than 10% less, but it tends to return to baseline shortly after the FMD. 

[Sibiriak]

6 hours ago, mccoy said:

Not necessarily so if the cycles are months apart.

Yes,  we just don't know.   Both the time between the fasts,  and the total number of consecutive fasts could influence the time to return to baseline, or possible shift in baseline

[Mike41]

Always thought occasional 5 day fasts didn’t make sense. It seems to me daily fasting by eating less or no animal protein and TRF would be more efficient. Would be an interesting clinical trial IAC.

[mccoy]

49 minutes ago, Mike41 said:

Always thought occasional 5 day fasts didn’t make sense. It seems to me daily fasting by eating less or no animal protein and TRF would be more efficient. Would be an interesting clinical trial IAC.

Fact is that, the theory (and experiments on mice and humans) suggests that some signals are triggered by fasting or eating drastically little for an X number of days, then refeeding.

Simple CR and TRF have not the same signaling effect. Also, fasts should be regular and not occasional, although the optimum frequency and duration of fasts are an unknown.

The above being said, what's best to do is also based upon individual situations and choices and degrees of belief.

Edited August 25, 2020 by mccoy

[Sibiriak]

48 minutes ago, mccoy said:

...some signals are triggered by fasting or eating drastically little for an X number of days, then refeeding. Simple CR and TRF have not the same signaling effect.

Yes,  longer fasts have different effects than short ones.   Both are good.  It all depends on your goals.    Personally, I like combining regular time-restricted eating ( I do two fasts per day, approx. 8 and 16hrs),  combined with periodic longer fasts (4 or more days).   I'm not absolutely  strict with the time-restricted eating.  Unlike Tomb, I find it best to be flexible and listen to my body.

In the following very short video clip (<3 minutes),   autophagy expert Guido Kroemer  states that, based on his studies, it takes 3-4 days of fasting  to induce  massive  autophagy in humans, and explains why fasting is very different for mice.

 

 

Edited August 25, 2020 by Sibiriak

[TomBAvoider]

Yet again we are talking about interventions - in this case fasting - as if it applies equally to all people. It does not. In fact, one important variable here is age. Apparently, for older people fasting has differential effects compared to people under 60. Like, fasting doesn't appear to trigger autophagy in the fasting elderly (something Peter Attia explored in a recent podcast). That's just one example. There are others. There are people on this list, fellow CRONies, who are in that age group. 

Again and again, you must specify the parameters of the effects of any intervention (including drugs) depending on individual circumstances - including age - and other factors that interact with it (diet, exercise, lifestyle choices, medications, genes, gender, race etc.).  

And yet, so rarely do we hear caveats and context from the various advocates of various interventions. But without such caveats, instead of health promotion, you might sustain serious damage. 

There is a great deal we still don't know, but we don't even take into account the things we do know, such as the fact that we need to specify individual circumstance before recommending any intervention. 

[Sibiriak]

1 hour ago, TomBAvoider said:

we are talking about interventions - in this case fasting - as if it applies equally to all people.

Yes, absolutely.  No intervention  applies equally to all people.  Age is  almost always a differentiating factor.   Thanks for the reminder.

 

On 8/24/2020 at 2:57 AM, TomBAvoider said:

I'm not anxious to elevate my IGF-I.       [...] I have not measured my IGF-I in a long time

 

Speaking of the age variable:   Given your advancing  age,   your IGF-1 might actually be on the low side. Maybe you shouldn't be concerned  at all about elevating it.  Maybe raising it would be a good thing.  Who knows?  You can't say without testing. Surprisingly,  Mccoy's came in very low.   

Edited August 26, 2020 by Sibiriak

[Sibiriak]

On 8/24/2020 at 12:26 PM, mccoy said:

Peter Attia described the changes associated to IGF-1 after one of his 'nothingburger' fasts (7 days keto+7 days water+7 days keto)

Btw,  Attia has apparently switched to fasting 3 days/ month (previously 7 days/quarter).   He also said he no longer does a strict keto diet,  but is  still low carb.

That's from a April 2020 podcast.

#108 - AMA #13: 3-day fasting, exogenous ketones, autophagy, and exercise for longevity

Also:

#89 – AMA #11: All things fasting

Edited August 26, 2020 by Sibiriak

[Ron Put]

12 hours ago, Sibiriak said:

He also said he no longer does a strict keto diet,  but is  still low carb.

In my personal opinion (based on my research), anyone who follows a long-term "strict keto diet" other than for very specific reasons (like epilepsy untreatable with available medication), loses credibility on the subject of good nutrition.

[Sibiriak]

On 8/25/2020 at 9:40 PM, Mike41 said:

Always thought occasional 5 day fasts didn’t make sense. It seems to me daily fasting by eating less or no animal protein and TRF

V. Longo et al.  provide some more detail on the physiological responses to fasting over time:

Fasting and cancer: molecular mechanisms and clinical application (2019)

Quote

Systemic response to fasting.

The response to fasting is orchestrated in part by the circulating levels of glucose, insulin, glucagon, growth hormone (GH), IGF1, glucocorticoids and adrenaline. During an initial post-absorptive phase, which typically lasts 6–24 hours, insulin levels start to fall, and glucagon levels rise, promoting the breakdown of liver glycogen stores (which are exhausted after approximately 24 hours) and the consequent release of glucose for energy. Glucagon and low levels of insulin also stimulate the breakdown of triglycerides (which are mostly stored in adipose tissue) into glycerol and free fatty acids. During fasting, most tissues utilize fatty acids for energy, while the brain relies on glucose and on ketone bodies produced by hepatocytes (ketone bodies can be produced from acetyl-CoA generated from fatty acid β-oxidation or from ketogenic amino acids).

In the ketogenic phase of fasting, ketone bodies reach concentrations in the millimolar range, typically starting after 2–3 days from the beginning of the fast. Together with fat-derived glycerol and amino acids, ketone bodies fuel gluconeogenesis, which maintains glucose levels at a concentration of approximately 4 mM (70 mg per dl), which is mostly utilized by the brain. Glucocorticoids and adrenaline also contribute to direct the metabolic adaptations to fasting, helping maintain blood sugar levels and stimulating lipolysis^20,21.

Notably, although fasting can at least temporarily increase GH levels (to increase gluconeogenesis and lipolysis and to decrease peripheral glucose uptake), fasting reduces IGF1 levels. In addition, under fasting conditions, IGF1 biological activity is restrained in part by an increase in the levels of insulin-like growth factor-binding protein 1 (IGFBP1), which binds to circulating IGF1 and prevents its interaction with the corresponding cell surface receptor²².

Finally, fasting decreases the levels of circulating leptin, a hormone predominantly made by adipocytes that inhibits hunger, while increasing the levels of adiponectin, which increases fatty acid breakdown^23,24. Thus, in conclusion, the hallmarks of the mammalian systemic response to fasting are low levels of glucose and insulin, high levels of glucagon and ketone bodies, low levels of IGF1 and leptin and high levels of adiponectin.

 

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Cellular response to fasting.

The response of healthy cells to fasting is evolutionarily conserved and confers cell protection, and at least in model organisms, has been shown to increase lifespan and healthspan^12,22,25-31. The IGF1 signalling cascade is a key signalling pathway involved in mediating the effects of fasting at the cellular level. Under normal nutrition, protein consumption and increased levels of amino acids increase IGF1 levels and stimulate AKT and mTOR activity, thereby boosting protein synthesis.

Vice versa, during fasting, IGF1 levels and downstream signalling decrease, reducing AKT-mediated inhibition of mammalian FOXO transcription factors and allowing these transcription factors to transactivate genes, leading to the activation of enzymes such as haem oxygenase 1 (HO1), superoxide dismutase (SOD) and catalase with antioxidant activities and protective effects^32-34.

High glucose levels stimulate protein kinase A (PKA) signalling, which negatively regulates the master energy sensor AMP-activated protein kinase (AMPK)³⁵, which, in turn, prevents the expression of the stress resistance transcription factor early growth response protein 1 (EGR1) (Msn2 and/or Msn4 in yeast)^26,36.

Fasting and the resulting glucose restriction inhibit PKA activity, increase AMPK activity and activate EGR1 and thereby achieve cell-protective effects, including those in the myocardium^22,25,26.

Lastly, fasting and FMDs (see below for their composition) also have the ability to promote regenerative effects (BOX 1) by molecular mechanisms, some of which have been implicated in cancer, such as increased autophagy or induction of sirtuin activity^22,37-49.

 

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Box 1

Regenerative effects of fasting and FMDs

Fasting and fasting-mimicking diets (FMDs) can cause substantial regenerative effects in mouse models. Mice fed an FMD starting at 16 months of age for 4 days twice a month show signs of adult neurogenesis, as measured by an increase in the proliferation of immature neurons and by the representation of neural precursors and neural stem cells²². This effect is accompanied by a reduction in circulating and hippocampal IGF1 and in hippocampal protein kinase A (PKA) activity and by a twofold increase in the hippocampal expression of the transcription factor NEUROD1, which is important for neuronal protection and differentiation³⁹.

An FMD also led to signs of skeletal muscle rejuvenation in mice — it countered the age-dependent decline in the expression of PAX7, a transcription factor that promotes myogenesis by regulating skeletal muscle satellite cell biogenesis and self-renewal^22,40.

Periodic fasting also promotes haematopoietic stem cell self-renewal and ameliorates age-dependent myeloid-bias in mice²⁵. IGF1 or PKA deficiency led to similar effects, highlighting a key role for these two signalling pathways in the pro-regenerative effects of fasting in the haematopoietic system.

Strikingly, periodic FMD cycles can also promote pancreatic β-cell regeneration, by reducing PKA and mTOR activity and by increasing the expression of developmental markers such as Nanog, Sox17, Sox2, Ngn3 and Ins, followed by Ngn3-mediated generation of insulin-producing β-cells⁴¹.

Fasting or FMDs induce autophagy, a naturally occurring, evolutionarily conserved mechanism that disassembles unnecessary or dysfunctional cellular components and allows survival by feeding cell metabolism and repair mechanisms^22,42,43. Studies show that autophagy improves healthspan, promotes longevity in mammals and contributes to the lifespan-prolonging effects of calorie-limited diets^44,45. In healthy cells, autophagy exerts multiple effects that converge to avoid the risk of malignant transformation, including the preservation of an optimal energetic and redox metabolism, the disposal of potentially harmful and genotoxic molecules, the fight of infections linked to cancer and the preservation of healthy stem cell compartments^46-48. A periodic FMD prevented the age-dependent accumulation of p62, a marker of defective autophagy, which suggests that the healthspan-promoting effects of FMDs are carried out at least in part by promotion of autophagic activity²².

Finally, sirtuins, which function as NAD⁺-dependent deacetylases and were ascribed protective and lifespan-extending effects in model organisms, also become more active during fasting^37,38.

The NAD⁺-producing enzyme nicotinamide phosphoribosyltransferase (NAMPT) and, consequently, intracellular NAD⁺ levels are upregulated during nutrient deprivation as well, further promoting the activity of mitochondrial sirtuins, particularly SIRT3 and SIRT4, and ultimately protecting cells from genotoxic agents, including chemotherapeutics⁴⁹.

 

Prolonged Fasting reduces IGF-1/PKA to promote hematopoietic stem cell-based regeneration and reverse immunosuppression (2015)
 

Quote

Prolonged fasting (PF) lasting 48–120 hours reduces pro-growth signaling and activates pathways that enhance cellular resistance to toxins and stress in mice and humans (Fontana et al., 2010b; Guevara-Aguirre et al., 2011; Holzenberger et al., 2003; Lee and Longo, 2011; Longo et al., 1997).

The physiological changes caused by PF are much more pronounced than those caused by calorie restriction or overnight fast, in part because of the requirement to fully switch to a fat- and ketone bodies-based catabolism after glycogen reserves are depleted during PF (Longo and Mattson, 2014).

 

 

Quote

[...] Recent studies revealed that HSCs rely heavily on the metabolic programs that prevent aerobic metabolism to maintain their quiescent state and self-renewal capacity (Ito et al., 2012; Takubo et al., 2013; Yu et al., 2013).

In the case of PF, the energy metabolism is switched progressively from a carbohydrate-based to a fat- and ketone body-based catabolism, which could contribute to HSC [hematopoietic stem cell] self-renewal, in agreement with findings that fatty-acid-oxidation promotes HSC asymmetric self-renewal over the symmetric commitment (Ito et al., 2012).

PKA is known to promote lineage specification of HSC through CREB and G9a (Chen et al., 2012; Yamamizu et al., 2012b). As inhibition of G9a has been a key strategy to promote reprogramming (Huangfu et al., 2008; Shi et al., 2008), the PF-induced down-regulation of G9a shown here may redirect cell fate through a similar process causing the induction in HSCs, analogously to that caused by G9a inhibition (Figure 5B)(Chen et al., 2012).

Recent studies also indicate that PKA can directly phosphorylate and negatively regulate FoxO1 (Chen et al., 2008; Lee et al., 2011), which has a profound role in stem cell stress resistance, self-renewal and pluripotency maintenance (Tothova et al., 2007; Zhang et al., 2011). Whereas PKA is implicated in stem cell differentiation, our study suggests that cycles of PF down-regulate IGF-1 and PKA to promote stem cell self-renewal.

[...] Our results indicate that cycles of an extreme dietary intervention represent a powerful mean to modulate key regulators of cellular protection and tissue regeneration but also provide a potential therapy to reverse or alleviate the immunosuppression or immunosenescence caused by chemotherapy treatment and aging, respectively, and possibly by a variety of diseases affecting the hematopoietic system and other systems and organs. 

 

Edited August 30, 2020 by Sibiriak