18 replies to this topic

[reason]

Boosting levels of fibroblast growth factor 21 (FGF21) has been shown to extend life in mice. Here, researchers classify it as a calorie restriction mimetic treatment:

Dietary or caloric restriction (DR or CR), typically a 30-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend lifespan and healthspan in diverse organisms, including mammals. Although the lifespan benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers healthspan benefits.

A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related lifespan-enhancing protocols. Increased expression of FGF21, a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends lifespan to a similar extent as DR in a recent study.

FGF21 may achieve these effects by attenuating GH/IGF1 signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents which is a critical component of alternate day fasting, a DR-like protocol that also increases lifespan and healthspan in mammals. Various drugs have been reported to induce FGF21 [but] of these, only metformin has been reported to extend lifespan in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression.

Perhaps the most parsimonious explanation is that high, possibly unphysiological, levels of FGF21 are needed to achieve maximum life- and healthspan benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and healthspan are warranted.

Link: http://www.ncbi.nlm....pubmed/23173578

<br> <br>View the full article

[YOLF]

So how long until we see a sublingual FGF21 spray?

[xEva]

The key words:

Increased expression of FGF21, a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals

So, no need to wait. You can stop eating now and in a week you'll have plenty of FGF21 in your system

[YOLF]

I can never stick to those fasting diets. I go a day or two w/o eating w/o realizing a few times a year though. But otherwise, I'm going to need the FGF21 spray

[Darryl]

Laeger, T., Henagan, T. M., Albarado, D. C., Redman, L. M., Bray, G. A., Noland, R. C., ... & Morrison, C. D. (2014). FGF21 is an endocrine signal of protein restriction. The Journal of Clinical Investigation, 124(124 (9)), 3913-3922.

 

 

Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.

 

Edited by Darryl, 23 August 2014 - 08:18 AM.

[niner]

I can never stick to those fasting diets. I go a day or two w/o eating w/o realizing a few times a year though.

 

Seriously?  You can go two days without eating and not realize it?  Wow.  Is there meth involved?

[Brett Black]

One of the issues pertaining to many of these anti growth/anabolic type interventions (e.g. GH, IGF-1 and fasting, calorie restriction and protein restriction), is the age at onset of the intervention, and how this might dramatically impact effectiveness. Often the intervention is started at the beginning of life or at least before adulthood, and often the result is a dramatic phenotypical/morphological change (e.g. dwarf mice, where growth is severely stunted.) There is also evidence in rodents that IGF-1 inhibition is only successful at extending lifespan when it occurs before adulthood. So the merits of adult-onset are questionable.

Another thing that concerns me is that there may be seriously negative side effects in humans from these same anti anabolic interventions that are not always evident in rodents. IGF-1 for instance, is known to have cardiovascular and neurological benefits and protective effects in humans. My understanding is that rodents, broadly, have more robust cardiovascular systems than humans (few rodents die or are disabled by CVD and stroke) so deleterious cardiovascular effects may not be detected, and it can obviously be very difficult to measure and compare neurological and cognitive differences in rodents in any great detail.

For anyone with an interest in this area, I highly recommend the following paper which examines the potential pros and cons inolved with these interventions:

1. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):587-98. doi: 10.1093/gerona/gls115.
Epub 2012 Apr 20.

Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian
aging: progress and controversies.

Sonntag WE(1), Csiszar A, deCabo R, Ferrucci L, Ungvari Z.

Author information:
(1)Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center,
Stanton L. Young Biomedical Research Center 1303, 975 NE 10th Street, Oklahoma
City, OK 74104, USA. william-sonntag@ouhsc.edu

Because the initial reports demonstrating that circulating growth hormone and
insulin-like growth factor-1 decrease with age in laboratory animals and humans,
there have been numerous studies related to the importance of these hormones for
healthy aging. Nevertheless, the role of these potent anabolic hormones in the
genesis of the aging phenotype remains controversial. In this chapter, we review
the studies demonstrating the beneficial and deleterious effects of growth
hormone and insulin-like growth factor-1 deficiency and explore their effects on
specific tissues and pathology as well as their potentially unique effects early
during development. Based on this review, we conclude that the perceived
contradictory roles of growth hormone and insulin-like growth factor-1 in the
genesis of the aging phenotype should not be interpreted as a controversy on
whether growth hormone or insulin-like growth factor-1 increases or decreases
life span but rather as an opportunity to explore the complex roles of these
hormones during specific stages of the life span.

PMCID: PMC3348498
PMID: 22522510 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/22522510
http://www.ncbi.nlm....les/PMC3348498/

[corb]

What about the fact that it shouldn't give significant benefits for humans anyway?

Because you make it sound like it's a pros vs cons thing and there's a good chance there's no or minimal pros for humans concerning lifespan.

 

http://www.ncbi.nlm....les/PMC1369270/

 

Unless you're obese or overweight.

 

http://www.plosone.o...al.pone.0047079

 

I suspect as far as healtspan is concerned eating normally (for non americans ) and doing exercise will probably have a greater benefit.

But if you want to fast feel free to do it, a lot of people do it for religious reasons and they seem to be ok so at least it doesn't kill you if you do it smart, that much we know.

 

[Logic]

I feel like a pimp for these guys, but I simply find their products very interesting.
There are 2 Calorie Restriction Mimetics on this page:
http://teamtlr.com/3...gevity-research

[Brett Black]

What about the fact that it shouldn't give significant benefits for humans anyway?
Because you make it sound like it's a pros vs cons thing and there's a good chance there's no or minimal pros for humans concerning lifespan.

Well, strong scientifc evidence just doesn't seem to there yet for humans, either pro or con, so I'm keeping an open mind. I find the following passage (from the paper I referenced) very interesting and relevant:

"Based on the literature, GH and IGF-1 have both beneficial and deleterious effects on specific pathologies that undoubtedly influence life span. Therefore, in many cases, the consequences of GH and IGF-1 deficiency are dependent on the species, background strain, and pathologies that the species or strain is susceptible. Those animals that are at risk for cancer, liver, or kidney disease will likely exhibit a shortened life span in response to elevated levels of GH and IGF-1, and we expect that those animals with reduced risk for these diseases will likely not exhibit increased life span in response to this intervention. Similarly, those species at risk for specific cardiovascular diseases (stroke, myocardial infarction, heart failure, vascular cognitive impairment) may benefit from elevated levels of these hormones. These effects are consistent with the classical actions of GH and IGF-1 being important anabolic agents that stimulate cell growth, proliferation, and tissue repair. Because cardiovascular diseases, metabolic diseases, and cancer are all important health issues in the elderly population, the effects of GH/IGF-1 pathway on human health span and life span are predictably complex."

http://www.ncbi.nlm....les/PMC3348498/

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I suspect as far as healtspan is concerned eating normally (for non americans ) and doing exercise will probably have a greater benefit.
But if you want to fast feel free to do it, a lot of people do it for religious reasons and they seem to be ok so at least it doesn't kill you if you do it smart, that much we know.

The increased autophagy aspect of fasting strongly intrigues me, yet as far as I know it doesn't seem to translate into any affect on lifespan (in rodents) if they are maintained on an otherwise equicaloric diet (ie they make up for the fasting periods with interleaved hypercaloric periods.) I don't know much about the current state of science regarding how/if fasting may influence healthspan; it's something I want to learn more about.

[drtom]

 

Laeger, T., Henagan, T. M., Albarado, D. C., Redman, L. M., Bray, G. A., Noland, R. C., ... & Morrison, C. D. (2014). FGF21 is an endocrine signal of protein restriction. The Journal of Clinical Investigation, 124(124 (9)), 3913-3922.

 

 

Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.

 

 

So the mechanism is not CR but protein restriction...and, I'm betting it's not even PR, but Methionine restriction.

So equal effects are probably obtainable by a low-Met diet (so you don't nee to endure the hunger pangs!)
 

[Darryl]

@drtom:

 

While methionine restriction is unique among amino acid restrictions in reducing mitochondrial radical generation (1), my understanding is that deficiencies of any amino acid may cause FGF21 expression. A possible mechanism, pieced together by Mark McCarty (2), is:

• Deficiencies of any amino acid cause accumulation of uncharged transfer RNA (rare in the protein replete state).
• Uncharged transfer RNA binds to GC nonderepressing 2 kinase (GCN2), inducing phosphorylation of eukaryotic initiation factor 2 (eIF2a) (3).
• Phosphorylated eIF2 increases transcription of activating transcription factor 4 (ATF4) (4).
• ATF4 binds to the two conserved ATF4 binding sites in the promotor of the FGF21 gene, increasing transcription (5)

From there, FGF21 can work its signalling magic, increasing adiponectin and blocking STAT5 activation and hepatic IGF-I expression.

 

The advantage of a low methionine or low lysine diet is that they're relatively achievable with certain plant based diets. This insight has certainly reduced my consumption of higher methionine soy products. 

 

(1) Caro, P., Gomez, J., Sanchez, I., Garcia, R., López-Torres, M., Naudí, A., ... & Barja, G. (2009). Effect of 40% restriction of dietary amino acids (except methionine) on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver. Biogerontology, 10(5), 579-592.

(2) McCarty, Mark F. (2014) GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets. Medical Hypotheses, 83(3),: 365–371.

(3) Hao, S., Sharp, J. W., Ross-Inta, C. M., McDaniel, B. J., Anthony, T. G., Wek, R. C., ... & Gietzen, D. W. (2005). Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science, 307(5716), 1776-1778.

(4) Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21.

(5) Ana, L. D. S. C., Pedro, F. M., & Diego, H. (2012). Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation.Biochemical Journal, 443(1), 165-171.

Edited by Darryl, 28 August 2014 - 05:41 PM.

[YOLF]

 

I can never stick to those fasting diets. I go a day or two w/o eating w/o realizing a few times a year though.

 

Seriously?  You can go two days without eating and not realize it?  Wow.  Is there meth involved?

 

No, it's usually when I'm working on a project of some kind, that or in the past, video games.

[jans]

Interesting to find an update to FGF21 tests, or is this from previous time -  http://www.hngn.com/...ing-in-mice.htm

 

Liver-derived metabolic hormone fibroblast growth factor 21 (FGF21) improves insulin sensitivity and extends lifespan in mice. Aging also compromises the adaptive immune system by reducing T-cell production from the thymus. In this paper, we describe a new immunological function of FGF21 as a regulator of T-cell production from thymus in aging. The overexpression of FGF21 prevents thymic lipoatrophy, which protects the mice from age-induced loss of naïve T cells. FGF21 expression in thymic epithelial cells and signaling in thymic stromal cells support thymic function in aging. Loss of FGF21 in mice increases lethality postirradiation and delays the reconstitution of thymus. Hence, we highlight FGF21 as an immunometabolic regulator that can be harnessed to delay immune senescence. http://www.pnas.org/...511113.abstract

[YOLF]

Has anyone seen a sublingual FGF21 yet?  

 

I also read recently that this stuff delays shrinkage of the thymus gland and protects youthful immune function. I'm wondering also if it can regenerate the thymus.

[Santi]

I haven't seen sublingual FGF21 yet. However acarbose which has been shown to increase lifespan in mice and attenuate the increase in AGEs increases FGF21.


http://www.ncbi.nlm....pubmed/25685364

[YOLF]

Very interesting. 

 

Still want sublingual FGF21 tho. I might order some foreign metformin and acarbose at some point, which do you think is better?

[Quattro64]

Just found out about fgf21 and it's potential on healthy life extension. Seems there is some speculation on betaine being an up-regulator and some evidence on alpha lipoic acid as well, tho I have no idea what type of dosing would be suggested for either, thoughts? Exciting that doctors may be able to prescribe this someday.

[YOLF]

Just found out about fgf21 and it's potential on healthy life extension. Seems there is some speculation on betaine being an up-regulator and some evidence on alpha lipoic acid as well, tho I have no idea what type of dosing would be suggested for either, thoughts? Exciting that doctors may be able to prescribe this someday.

Would love to see some papers on this, I'm already taking both. I have a feeling I know of some metformin mimetics too. Still, I'd rather just take the stuff sublingually, cofactors may only take us so far and might just be redistributing our aging pathologies. Periodically running a few months of some FGF21 or maybe some thymosin? should be safe? and effective at letting our immune system kill off some old cells.