Jump to content
mikeccolella

Metformin and growth hormone reverse aging in humans

Recommended Posts

Very interesting.

But as we've already witnessed the previous wave of GH hype, I'd say it's probably prudent to see this replicated and longer term studies showing the safety of such supplementation.

Share this post


Link to post
Share on other sites

Hi Tom!

I wouldn't touch the stuff.  GH is anabolic; it will build muscles, but will speed up the aging process.

The underlying error is whatever criteria are being used in whoever's definition of "Biological Aging".

  --  Saul 

Share this post


Link to post
Share on other sites

Yes, Saul, I agree - I wouldn't go for it at this time. Too many unknowns. GH of course can be quite dangerous, but we don't even know much about metformin. I've been researching metformin, and it's very tricky to try to get benefits if you are a healthy normal weight individual. For example, metformin blunts the benefits of exercise, it can be completely ineffective if your diet composition isn't just right, and dosage is a big question. The latest thinking is to pulse metformin - take only on days you are not exercising - but at what dosage is not clear at all. 

Bottom line, even with well-researched stuff like metformin, there is a whole lot we don't know, and the deeper you dig in, the more confused the picture becomes. I wouldn't just fool around with GH willy-nilly, we have no clue about dosage and protocol and longitudinal outcomes.

Share this post


Link to post
Share on other sites

Also how do we know metformin is any better than other BAT activators? We'll probably never see a comparative study. 

Share this post


Link to post
Share on other sites

Hi Tom!

I generally avoid all supplements, except for supplementing nutrients that may be inadequately addressed in my diet.  Metformin is not a nutrient -- I avoid it.

GH is, IMO, REALLY something to avoid -- like testosterone and IGF1, it is anabolic.  I don't take these muscle building supplements; IMO, the right way to maintain adequate muscle whether or not on CR, is with vigorous aerobic exercise, which I do daily six days a week.

Anabolic substances, while building muscle, are likely to reduce both healthspan and lifespan.

Tom, I'm sure that you know this -- this post is mainly targeted for newbies.

Share this post


Link to post
Share on other sites

Wow, I’m surprised at such breezy dismissals of an actual anti-aging study in real, live and healthy human beings. Isn’t this what we want? To slow, stop, reverse human aging?

Shouldn’t any paper that states “....we conducted what may be the first human clinical trial designed to reverse aspects of human aging...” capture your attention and admiration? Your imagination should be stimulated for what good things may be ahead in this young field (that’s obviously so egregiously underfunded and under supported).

The recombinant human growth hormone (rhGH) Fahy used in this work was targeted “to prevent or reverse signs of immunosenescence in a population of 51‐ to 65‐year‐old healthy men.”

From the paper: “Because GH‐induced hyperinsulinemia (Marcus et al., 1990) is undesirable and might affect thymic regeneration and immunological reconstitution, we combined rhGH with both dehydroepiandrosterone (DHEA) and metformin in an attempt to limit the “diabetogenic” effect of GH (Fahy, 2003, 2010; Weiss, Villareal, Fontana, Han, & Holloszy, 2011). DHEA has many effects, in both men and women, that oppose deleterious effects of normal aging (Cappola et al., 2009; Forti et al., 2012; Shufelt et al., 2010; Weiss et al., 2011). Metformin is a powerful calorie restriction mimetic in aging mice (Dhahbi, Mote, Fahy, & Spindler, 2005) and has been proposed as a candidate for slowing aging in humans (Barzilai, Crandall, Kritchevsky, & Espeland, 2016). Neither DHEA (Riley, Fitzmaurice, & Regelson, 1990) nor metformin are known to have any thymotrophic effects of their own.”

This is a wonderful study — albeit humble and hard-fought due to funding limitations — and of course it needs replication. But like WTF.... But why aren’t you excited?! This is an effort — a decade or so in the making — in which Fahy et al “...observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study)...”

I feel like this is a moment you should be supportive of these baby steps, not dismissive. This very protocol may lead to actual effective human interventions that someday gonna save yo’ hide!

And. It’s. Not. In. Genetically Altered Rodents! Hey there, happy: get happier.

Share this post


Link to post
Share on other sites

Hi Sthira!

23 minutes ago, Sthira said:

Shouldn’t any paper that states “....we conducted what may be the first human clinical trial designed to reverse aspects of human aging...” capture your attention and admiration?

No.  Not all anti-aging studies are created equally.

😉

  --  Saul

Share this post


Link to post
Share on other sites
1 hour ago, Saul said:

Hi Sthira!

No.  Not all anti-aging studies are created equally.

😉

  --  Saul

Hah! While I agree that based on past HGH long term studies, this needs to be replicated in a larger group and safety should be determined over a longer period, before we get too excited.

But for what it is (including the financial interests disclosed by some of the researchers), it's actually not a bad study. And it is certainly a bit more rigorous and based on somewhat better methodology than the Luigi CR study discussed in the testosterone thread 🙂

Edited by Ron Put

Share this post


Link to post
Share on other sites

Here's Dr. Peter Attia's thoughts on this study:

Greetings -

“First hint that body’s ‘biological age’ can be reversed.” 

In a world where the population aged 60 or over doubled in the last 30 years, and is expected to double again by 2050, how’s that for a sensational headline? The story, written in the journal Nature, is referring to a study published by Aging Cell. Amazingly, only 137 of you sent it to me within the first 24 hours of its release. 

Nine healthy men, given a cocktail of human growth hormone (hGH), metformin, DHEA, vitamin D3, and zinc for 1-year, shed about 2.5 years off their biological ages, according to an analysis of their epigenome.

As a result of this study, I’ve had more people than usual ask the following questions:

Should I be taking hGH? Should I be taking metformin? Should I be taking DHEA?

To address these questions (and others) will be a bit of an undertaking, so I’m breaking this topic up into at least two emails. In today’s email, I want to explain the study’s purpose, how it was done, what it found, as well as some of the nuts and bolts behind it, and—most importantly—propose a framework for evaluating studies in general. I’ve covered a lot of the groundwork in the Studying Studies series so I may sound a little like a broken record in places. That said, if you are tired of being held hostage by the media’s interpretation of science, you will need to buck up and learn this stuff. The Studying Studies series is the starting point. I realize it may seem like Groundhog Day for you to see more prose from me about how to think about studies rather than the tactical bits we think we can immediately extract and employ from them. Just remember, it’s better to learn how to fish than to be given … you get it. 

On to the study. 

The stated purpose was to investigate the possibility that using hGH in a population of men in their 50s and early 60s can prevent or reverse signs of the gradual deterioration of the immune system that has been attributed to natural age development (i.e., immunosenescence). The trial, dubbed Thymus Regeneration, Immunorestoration, and Insulin Mitigation, or TRIIM, reveals its aims. (Note that nothing in the initial aim of the study dealt with assessing the impact of the hormone/drug cocktail on the epigenome, for which all the attention has been generated.)

The thymus, a gland located in the middle of the upper chest, converts white blood cells from bone marrow into T-cells, which play a central role in the immune response. The “T” in T-cells is named after the thymus. As it turns out, the thymus reaches its maximum size by the end of the first year of life. After that, the thymus decreases in size and activity, particularly after puberty, in a process referred to as thymic involution. Along with the decrease in size and activity of the immune system with age comes an associated functional decline. The lead investigator of the study, Greg Fahy, wanted to see if he could regenerate the thymus and restore immune system function using hGH.

All things equal, a more youthful immune system would suggest greater longevity. But there was a catch with using hGH. The investigators worried that using hGH to regenerate the thymus might induce hyperinsulinemia (high insulin) and noted a “diabetogenic” effect of growth hormone. Hyperinsulinemia and diabetes are obviously not desired side effects, regardless of how much thymic regeneration takes place. So Fahy and his colleagues added metformin and DHEA to try and counter these potential effects. Vitamin D3 and zinc were also added as a hedge against cancer and inactive thymulin, according to Fahy (personal communication, email).

It’s not a surprise that the investigators chose metformin as a drug that can aid in “Insulin Mitigation” (the “IM” in TRIIM; for a nice overview of why, revisit the interview with Nir Barzilai), but DHEA? This was news to me. After doing a little, I mean a lot of digging, I would say there is not much in the way of evidence supporting the use of DHEA as an insulin lowering agent. According to a related article, it appears Fahy was working off his own hypothesis. Young people have higher growth hormone without an increase in insulin, and Fahy believed this to be due to them having higher levels of DHEA. Fahy tested this on himself by taking hGH alone for a week and found his insulin levels elevated by 50%. He then added DHEA and the increase was apparently reversed. 

In the TRIIM study 9 men, ages 51-65, first took hGH alone (0.015 mg/kg, or ~3 IU for a person weighing 70 kg) 3-4 times per week for one week and then added DHEA (50 mg) the next week, similar to Fahy’s n=1.  The week after that, the same doses of hGH and DHEA were combined with metformin (500 mg). At the start of the fourth week, the doses were individualized based on each participant’s particular responses. (To put the hGH dosing into context, while it’s individualized, athletes using it for performance enhancement may take 10-25 IU 3-4 times a week and “longevity” clinics may prescribe somewhere in the ballpark of 1-2 IU/day.) The goal of this titration approach was to maximize IGF-1 and minimize insulin by varying each of the hormones and drugs. The study didn’t reveal what the effect DHEA hay have had after week 2, so we contacted Fahy to check. He wrote that the results with DHEA were qualitatively the same but quantitatively different, with each person having their own specific response (personal communication, email).

It’s important to highlight that not only was this study multifaceted in the number of independent variables introduced (i.e., hGH, metformin, DHEA, vitamin D3, zinc), it was also personalized, since the subjects did not all receive the same dose of each agent. It’s possible (actually, likely) that all nine subjects were consuming a different cocktail in terms of the dosing of hGH, DHEA, and metformin. Also, it was a very small sample size and lacked a control group, consisting entirely of 9 healthy (see Supplement 2 for exclusion criteria) 51-65-year-old men.

So why, you might (rightly) ask, all the media hype for a very small, not especially well-controlled preliminary/exploratory study? 

The investigators reported a mean “epigenetic age” approximately 1.5 years less than baseline after the 1-year intervention. In other words, their epigenetic age got 1.5 years younger while their chronological age obviously went up another year. For example, let’s say “John” entered the trial with a chronological and epigenetic age of 60. After the trial his chronological age is 61 and his epigenetic age is 58.5. Presumably, he increased his life expectancy (LE) by ~2.5 years, or got ~2.5 years younger biologically, depending on how you look at it. And it’s exactly for this reason that this study is being talked about at all. 

Which brings us to the framework I would suggest you apply to every study you read or attempt to evaluate. In a study like this, lacking a control group and utilizing a surrogate outcome (i.e., something other than actual morbidity or mortality), such an analysis is essential. Let’s walk through the possible outcomes with respect to the intervention (the independent variables) and biological aging using the epigenetic clocks (the dependent variable). So now consider a 2x2 matrix of the following scenarios: 

(i) the dependent variable (the clock) is a correct (i.e., representative) output measurement versus it is not. 

(ii) the independent variables (the cocktail of inputs) did versus did not lead to the outcome we saw. 

Again, the former question is necessary whenever evaluating a study with surrogate (i.e., not “hard”) outcomes and the latter question is essential in the absence of a control group.

The exercise, then, is to evaluate each of the 4 quadrants in this matrix and ultimately decide, for yourself, which one has the highest probability of being correct. This is the scientific method. It is not absolute. There are no “proofs.” It’s all about probabilities. Let’s start with the assumption that there was no foul play by anyone involved in the study. In this case, either:
1. The intervention accounted for the improvement, or 
2. Something other than the intervention accounted for the improvement. 
In the first case, there are also many scenarios, and in the latter, there are also many scenarios. In the first case, it may be that the metformin alone accounted for the improvement, or the hGH alone, or there was a synergistic effect between the hGH, DHEA, and metformin, or perhaps one compound in the cocktail was detrimental, but the other compounds more than made up for it. And, remember, not only was there no control group, there was no consistency in the intervention. Everyone got their own signature cocktail. In the second case, it could be the Hawthorne effect at play. This is a type of bias where individuals change aspects of their behavior in response to knowing that they’re being observed. Maybe the participants changed their eating, sleeping, or exercising, for example, which confounded the experiment.

So this tells us how to consider the inputs to the study, but what about the output? Next, we consider if there was some sort of epigenetic clock malfunction? Here, we’ll consider the next two scenarios:
3. The clock estimate accurately represents biological age, or
4. The clock estimate is inaccurate.
Either we’re not being fooled and the clock is accurately picking up a change in mortality risk in this study or we’re being fooled and the clock is malfunctioning for some reason. We’ll pick this up next week (or the week after) to assess the likelihood of each matrix quadrant. 

Oh, and I almost forgot, what may have gotten lost in the shuffle is whether the treatment showed promise for TRIIM, the intended aim of the study. After 1-year of treatment, there was “highly significant” evidence of a restoration of thymic functional mass along with improvements in age-related immunological parameters, based on MRI imaging and favorable changes in monocytes and T-cell changes. Insulin levels were reportedly controlled, so as far as preliminary studies go, it’s an intriguing finding, with certainly a lot more to learn.

- Peter

Share this post


Link to post
Share on other sites
Quote

So why, you might (rightly) ask, all the media hype for a very small, not especially well-controlled preliminary/exploratory study? 

Clickbait headlines,  increased readership, advertising revenues.

Share this post


Link to post
Share on other sites
58 minutes ago, Saul said:

I have a much lesser opinion of Peter Attia.

I don't agree with all of his conclusions but I respect his effort to be objective and I like that he emphasizes what is uncertain.

As for the current debate on this study using exogenous GH plus metformin to reduce the tendency to hyperinsulinemia I find it curious that there has been little mention that there are more natural ways of increasing GH such as fasting, exercise and sauna which simultaneously lower insulin.  My guess is when GH rises as part of evolved physiological responses to diet and other stresses it is less likely to result in the profound harms that can come from injecting GH when it is naturally suppressed in a state of excess serum energy substrates.  I would be surprised if this cocktail produced more favorable results than a carefully constructed protocol of lifestyle factors.

Edited by Todd Allen

Share this post


Link to post
Share on other sites
15 hours ago, Ron Put said:

But for what it is (including the financial interests disclosed by some of the researchers), it's actually not a bad study.

Financially motivated researchers. Relatively short-term, heterogeneous, multi-pronged intervention. Small test population. No control group. Post hoc analysis based on dubious surrogate endpoint.

Yeah - real high quality...

--Dean

Share this post


Link to post
Share on other sites
4 hours ago, Dean Pomerleau said:

Financially motivated researchers. Relatively short-term, heterogeneous, multi-pronged intervention. Small test population. No control group. Post hoc analysis based on dubious surrogate endpoint.

Yeah - real high quality...

--Dean

I don't necessarily hold Attia in the highest esteem, but the last sentence excerpted by Todd makes the bottom line point, IMO:

"After 1-year of treatment, there was “highly significant” evidence of a restoration of thymic functional mass along with improvements in age-related immunological parameters, based on MRI imaging and favorable changes in monocytes and T-cell changes. Insulin levels were reportedly controlled, so as far as preliminary studies go, it’s an intriguing finding, with certainly a lot more to learn."

Share this post


Link to post
Share on other sites

David Sinclair has a new book out, so he's hitting the marketing circuit, including podcasts such as Joe Rogan, and the above mentioned Peter Attia (the latest episode on the Peter Attia podcast). 

I personally am somewhat skeptical about the accuracy of the Horvath Clock wrt. supposed biological age. Sinclair seems all-in on the clock, but he's wont to let his enthusiasm get ahead of the data as we've seen with the resveratrol debacle what with its early claimed promise (by Sinclair and the pop press - but also big pharma got hoodwinked into acquiring his startup, so at least Sinclair got rich - meanwhile the resveratrol hype, into which I never bought into for a single second, has now thankfully died down, with, lol, the pharma company left holding the bag, lol).

The more one learns about that study the murkier things get, what with some apparently additional interventions of zinc and vit. D, (communicated privately by Fahy to Attia through email, lol) it's a big mess. I'm staying far away from this one.

That said, yes, it's nice that at least it's in humans, even if there are no controls and the grand number of subjects is 9, lol.

Share this post


Link to post
Share on other sites

David Sinclair has a new book out, so he's hitting the marketing circuit, including podcasts such as Joe Rogan, and the above mentioned Peter Attia (the latest episode on the Peter Attia podcast). 

I personally am somewhat skeptical about the accuracy of the Horvath Clock wrt. supposed biological age. Sinclair seems all-in on the clock, but he's wont to let his enthusiasm get ahead of the data as we've seen with the resveratrol debacle what with its early claimed promise (by Sinclair and the pop press - but also big pharma got hoodwinked into acquiring his startup, so at least Sinclair got rich - meanwhile the resveratrol hype, into which I never bought into for a single second, has now thankfully died down, with, lol, the pharma company left holding the bag, lol).

The more one learns about that study the murkier things get, what with some apparently additional interventions of zinc and vit. D, (communicated privately by Fahy to Attia through email, lol) it's a big mess. I'm staying far away from this one.

That said, yes, it's nice that at least it's in humans, even if there are no controls and the grand number of subjects is 9, lol.

Share this post


Link to post
Share on other sites

Longevity science has a history of being ignored, marginalized, underfunded, mocked by the real scientists doing the important science. s/

Should I be surprised, though, to see that tradition reflected in here of all places? Gentle reminder that you’re posting on a Calorie Restriction Society Forum. And CR or CRON or CRAN in the bodies of CRONnies or CRANnies or whoever you are is one big ole self-induced behavioral experiment in under-eating, while not-knowing much “science” about anything human at all:

“FAQ How Many Calories Should I Eat? What's My Goal Weight? What's My Setpoint? What "%CR" Am I?

“By Michael R, June 6, 2017 in CR Practice Setpoint

“People starting CR would very much like to have definitive, hard-and-fast answers to these questions, and unfortunately, there just isn't any way to give one in free-living humans! No one can tell you the exact point at which you're "on CR" or what "%CR" you are. These are guidelines and principles for entering the "CR continuum."

And we don’t even know if this continuum (and I’m on it, for sure, I’m experimenting with CR at 20% for years now...) we don’t know if this is a healthy program, an unhealthy program — we don’t know much. Will I live a longer, healthier life because I’m eating less? And we’ll never know because the conventional science you desire is just too limited.

My point here in this stuffy old room is that it’s gonna take revolutionary people creating new windows — taking risks, stepping outside boundaries, doing work that will be sidelined and mocked by the establishment for more years. 

Advances in longevity science are gonna require best-effort attempts that sometimes simply must be “...Relatively short-term, heterogeneous, multi-pronged intervention. Small test population. No control group. Post hoc analysis based on dubious surrogate endpoint...” because what else was Fahy supposed to do here? With limited funding and support? Should they have given up? Or just do the best they could have done within this harsh desert of limited funding?

The only reason this study doesn’t meet the high standards you desire is due to lack of funding. Think Fahy didn’t want to create the best possible effort to regrow the involuted human thymus? He didn’t have the hundreds of millions required.

You get what you pay for, and now you get less and so you throw stones. Did any of you contribute to this work? Or have you contributed to any budding, revolutionary human longevity science? 

I get it if you can’t because you’re poor. But if you’ve got it, did you donate something? Can you now support someone else attempting something revolutionary that still may not meet your exacting standards?

Sure, throw shade on budding efforts — reminder that SENS is budding — mock it, disparage the people doing what’s necessary to try to help you. Part of tired out old tradition.

And really — evidently claiming Fahy spent a decade of his life for clickbait or some speculative biotech stock gains — I mean, wow... You should be ashamed, frankly. We should invite Fahy for an AMA here. 

de Grey: 

“Public enthusiasm for new advances is a key ingredient in influencing policy-makers to stimulate follow-up work with suitable funding, and it can be achieved far faster now that interested non-specialists can explore new research autonomously and can also be appealed to directly by scientists.”

Share this post


Link to post
Share on other sites

Sthira,

1 hour ago, Sthira said:

Should they have given up? Or just do the best they could have done within this harsh desert of limited funding?

I don't think anyone is suggesting they should have given up, or give up now. At least I'm not. Small, exploratory studies and even self-experimentation (e.g. Liz Parrish or our own "small N" foray into human CR) have their place. But the kind of hype this small study has generated (whether intentionally by the researchers or not) is undeserved and potentially harmful in several ways.

Better trials than this one have shown GH replacement in older people isn't very helpful and appears to have "worrisome side effects" [1][2]. Mutant mice with naturally low GH levels live longer [3] and GH replacement in these long-lived mice shorten their lifespan [4].

Even metformin is not without potential risks and downsides. As Tom pointed out, metformin treatment appears to counteract some of the beneficial effects of exercise. To quote from that study [5]:

These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

It is possible that the cocktail of GH and Metformin (+ DHEA + Vitamin D? + Zinc?) will turn out to be a magic elixer, and will counteract each other's downsides. If well-informed people want to throw the dice and try the combination, they are welcome to.

But I wouldn't want to bet my life or my health on it. It would be nice to see this cocktail extend lifespan in rodents before considering it.

My fear is that some people will see the media hype and start such a regime without full understanding of the potential risks and downsides, and end up harming themselves in the same way ill-informed Tesla owners over-rely on Autopilot due to the hype and end up repeatedly decapitating themselves.

You seem to suggest (via your Aubrey quote) that "public enthusiasm" is good and necessary to make progress. But unwarranted hype like this also has the real potential to result in disappointment and backlash when the early promise doesn't bear up under further scrutiny. Worse it has the potential to distract attention from (and funding for) more promising approaches to slow aging and age-related disease like those being pursued by SENS researchers. For example, efforts to clear the bloodstream of 7-ketocholesterol which is a large factor in our number one killer, CVD.

--Dean

---------------------

[1] Best Pract Res Clin Endocrinol Metab. 2017 Feb;31(1):113-125. doi:

10.1016/j.beem.2017.02.005. Epub 2017 Feb 24.

GH and ageing: Pitfalls and new insights.

Bartke A(1), Darcy J(2).

Author information: 
(1)Department of Internal Medicine, Southern Illinois University School of
Medicine, Springfield, IL, USA. Electronic address: abartke@siumed.edu.
(2)Department of Internal Medicine, Southern Illinois University School of
Medicine, Springfield, IL, USA; Department of Medical Microbiology, Immunology
and Cell Biology, Southern Illinois School of Medicine, Springfield, IL, USA.

The interrelationships of growth hormone (GH) actions and aging are complex and
incompletely understood. The very pronounced age-related decline in GH secretion 
together with benefits of GH therapy in individuals with congenital or adult GH
deficiency (GHD) prompted interest in GH as an anti-aging agent. However, the
benefits of treatment of normal elderly subjects with GH appear to be marginal
and counterbalanced by worrisome side effects.
In laboratory mice, genetic GH
deficiency or resistance leads to a remarkable extension of longevity accompanied
by signs of delayed and/or slower aging. Mechanisms believed to contribute to
extended longevity of GH-related mutants [with LOW GH - DP] include improved anti-oxidant defenses, 
enhanced insulin sensitivity and reduced insulin levels, reduced inflammation and
cell senescence, major shifts in mitochondrial function and energy metabolism,
and greater stress resistance
. Negative association of the somatotropic signaling
and GH/insulin-like growth factor 1 (IGF-1)-dependent traits with longevity has
also been shown in other mammalian species. In humans, syndromes of GH resistance
or deficiency have no consistent effect on longevity, but can provide striking
protection from cancer, diabetes and atherosclerosis
. More subtle alterations in 
various steps of GH and IGF-1 signaling are associated with reduced old-age
mortality, particularly in women and with improved chances of attaining extremes 
of lifespan. Epidemiological studies raise a possibility that the relationship of
IGF-1 and perhaps also GH levels with human healthy aging and longevity may be
biphasic. However, the impact of somatotropic signaling on neoplastic disease is 
difficult to separate from its impact on aging, and IGF-1 levels exhibit opposite
associations with different chronic, age-related diseases.

Copyright © 2017 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.beem.2017.02.005 
PMCID: PMC5424628
PMID: 28477727  [Indexed for MEDLINE]
 

---------------------

[2] Ann Intern Med. 2007 Jan 16;146(2):104-15.

Systematic review: the safety and efficacy of growth hormone in the healthy
elderly.

Liu H(1), Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, Hoffman AR.

Author information: 
(1)Stanford University, Stanford, California 94305-6019, USA. hauliu@stanford.edu

Comment in
    Nat Clin Pract Endocrinol Metab. 2007 Jul;3(7):508-9.

BACKGROUND: Human growth hormone (GH) is widely used as an antiaging therapy,
although its use for this purpose has not been approved by the U.S. Food and Drug
Administration and its distribution as an antiaging agent is illegal in the
United States.
PURPOSE: To evaluate the safety and efficacy of GH therapy in the healthy
elderly.
DATA SOURCES: The authors searched MEDLINE and EMBASE databases for
English-language studies published through 21 November 2005 by using such terms
as growth hormone and aging.
STUDY SELECTION: The authors included randomized, controlled trials that compared
GH therapy with no GH therapy or GH and lifestyle interventions (exercise with or
without diet) with lifestyle interventions alone. Included trials provided GH for
2 weeks or more to community-dwelling participants with a mean age of 50 years or
more and a body mass index of 35 kg/m2 or less. The authors excluded studies that
evaluated GH as treatment for a specific illness.
DATA EXTRACTION: Two authors independently reviewed articles and abstracted data.
DATA SYNTHESIS: 31 articles describing 18 unique study populations met the
inclusion criteria. A total of 220 participants who received GH (107
person-years) completed their respective studies. Study participants were elderly
(mean age, 69 years [SD, 6]) and overweight (mean body mass index, 28 kg/m2 [SD, 
2]). Initial daily GH dose (mean, 14 microg per kg of body weight [SD, 7]) and
treatment duration (mean, 27 weeks [SD, 16]) varied. In participants treated with
GH compared with those not treated with GH, overall fat mass decreased (change in
fat mass, -2.1 kg [95% CI, -2.8 to -1.35] and overall lean body mass increased
(change in lean body mass, 2.1 kg [CI, 1.3 to 2.9]) (P < 0.001), and their weight
did not change significantly (change in weight, 0.1 kg [CI, -0.7 to 0.8]; P =
0.87). Total cholesterol levels decreased (change in cholesterol, -0.29 mmol/L
[-11.21 mg/dL]; P = 0.006), although not significantly after adjustment for body 
composition changes. Other outcomes, including bone density and other serum lipid
levels, did not change. Persons treated with GH were significantly more likely to
experience soft tissue edema, arthralgias, carpal tunnel syndrome, and
gynecomastia and were somewhat more likely to experience the onset of diabetes
mellitus and impaired fasting glucose.

LIMITATIONS: Some important outcomes were infrequently or heterogeneously
measured and could not be synthesized. Most included studies had small sample
sizes.
CONCLUSIONS: The literature published on randomized, controlled trials evaluating
GH therapy in the healthy elderly is limited but suggests that it is associated
with small changes in body composition and increased rates of adverse events. On 
the basis of this evidence, GH cannot be recommended as an antiaging therapy.

DOI: 10.7326/0003-4819-146-2-200701160-00005 
PMID: 17227934  [Indexed for MEDLINE]
 

---------------------

[3] 

1. Curr Top Dev Biol. 2004;63:189-225.

Life extension in the dwarf mouse.

Bartke A(1), Brown-Borg H.

Author information: 
(1)Geriatrics Research, Department of Medicine, Southern Illinois University
School of Medicine, Springfield, Illinois 62794, USA.

Ames dwarf mice and Snell dwarf mice lack growth hormone (GH), prolactin (PRL),
and thyroid-stimulating hormone (TSH), live much longer than their normal
siblings, and exhibit many symptoms of delayed aging. "Laron dwarf mice,"
produced by targeted disruption of the GH receptor/GH-binding protein gene
(GHR-KO mice), are GH resistant and also live much longer than normal animals
from the same line.
Isolated GH deficiency in "little" mice is similarly
associated with increased life span, provided that obesity is prevented by
reducing fat content in the diet. Long-lived dwarf mice share many phenotypic
characteristics with genetically normal (wild-type) animals subjected to
prolonged caloric restriction (CR) but are not CR mimetics. We propose that
mechanisms linking GH deficiency and GH resistance with delayed aging include
reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1), reduced
secretion of insulin, increased hepatic sensitivity to insulin actions, reduced
plasma glucose, reduced generation of reactive oxygen species, improved
antioxidant defenses, increased resistance to oxidative stress, and reduced
oxidative damage. The possible role of hypothyroidism, reduced body temperature, 
reduced adult body size, delayed puberty, and reduced fecundity in producing the 
long-lived phenotype of dwarf mice remains to be evaluated. An important role of 
IGF-1 and insulin in the control of mammalian longevity is consistent with the
well-documented actions of homologous signaling pathways in invertebrates.

DOI: 10.1016/S0070-2153(04)63006-7 
PMID: 15536017  [Indexed for MEDLINE]

----------------------

[4]  FASEB J. 2010 Dec;24(12):5073-9. doi: 10.1096/fj.10-163253. Epub 2010 Aug 18.

Early life growth hormone treatment shortens longevity and decreases cellular
stress resistance in long-lived mutant mice.

Panici JA(1), Harper JM, Miller RA, Bartke A, Spong A, Masternak MM.

Author information: 
(1)Department of Internal Medicine, Geriatrics Research, Southern Illinois
University School of Medicine, Springfield, Illinois, USA.

Hypopituitary Ames dwarf mice were injected either with growth hormone (GH) or
thyroxine for a 6-wk period to see whether this intervention would reverse their 
long life span or the resistance of their cells to lethal stresses. Ames dwarf
mice survived 987 ± 24 d (median), longer than nonmutant control mice (664 ± 48),
but GH-injected dwarf mice did not differ from controls (707 ± 9). Fibroblast
cells from Ames dwarf mice were more resistant to cadmium than cells from
nonmutant controls (LD(50) values of 9.98 ± 1.7 and 3.9 ± 0.8, respectively), but
GH injections into Ames dwarf mice restored the normal level of cadmium
resistance (LD(50)=5.8 ± 0.9). Similar restoration of normal resistance was
observed for fibroblasts exposed to paraquat, methyl methanesulfonate, and
rotenone (P<0.05 in each case for contrast of GH-treated vs. untreated dwarf
mice; P<0.05 for dwarf vs. nonmutant control mice.) T4 injections into Ames dwarf
mice, in contrast, did not restore normal life span. We conclude that the
remarkable life-span extension of Ames dwarf mice, and the stress resistance of
cells from these mice, depends on low levels of GH exposure in juvenile and very 
young adult mice.

DOI: 10.1096/fj.10-163253 
PMCID: PMC2992365
PMID: 20720157  [Indexed for MEDLINE]
 

----------------------

[5] Aging Cell. 2019 Feb;18(1):e12880. doi: 10.1111/acel.12880. Epub 2018 Dec 11.

Metformin inhibits mitochondrial adaptations to aerobic exercise training in
older adults.

Konopka AR(1)(2), Laurin JL(2), Schoenberg HM(2), Reid JJ(2), Castor WM(2), Wolff
CA(2), Musci RV(2), Safairad OD(1), Linden MA(2), Biela LM(2), Bailey SM(3),
Hamilton KL(2), Miller BF(2)(4).

Author information: 
(1)Department of Kinesiology and Community Health, University of Illinois
Urbana-Champaign, Urbana, Illinois.
(2)Department of Health and Exercise Science, Colorado State University, Fort
Collins, Colorado.
(3)Department of Environmental & Radiological Health Sciences, Colorado State
University, Fort Collins, Colorado.
(4)Aging and Metabolism Research Program, Oklahoma Medical Research Foundation,
Oklahoma City, Oklahoma.

Metformin and exercise independently improve insulin sensitivity and decrease the
risk of diabetes. Metformin was also recently proposed as a potential therapy to 
slow aging. However, recent evidence indicates that adding metformin to exercise 
antagonizes the exercise-induced improvement in insulin sensitivity and
cardiorespiratory fitness. The purpose of this study was to test the hypothesis
that metformin diminishes the improvement in insulin sensitivity and
cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting
skeletal muscle mitochondrial respiration and protein synthesis in older adults
(62 ± 1 years). In a double-blinded fashion, participants were randomized to
placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET.
Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 
24-hr ambulant mean glucose, and glycemic variability. However, metformin
attenuated the increase in whole-body insulin sensitivity and VO2 max after AET. 
In the metformin group, there was no overall change in whole-body insulin
sensitivity after AET due to positive and negative responders. Metformin also
abrogated the exercise-mediated increase in skeletal muscle mitochondrial
respiration. The change in whole-body insulin sensitivity was correlated to the
change in mitochondrial respiration. Mitochondrial protein synthesis rates
assessed during AET were not different between treatments. The influence of
metformin on AET-induced improvements in physiological function was highly
variable and associated with the effect of metformin on the mitochondria. These
data suggest that prior to prescribing metformin to slow aging, additional
studies are needed to understand the mechanisms that elicit positive and negative
responses to metformin with and without exercise.

© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley
& Sons Ltd.

DOI: 10.1111/acel.12880 
PMCID: PMC6351883
PMID: 30548390 
 

Share this post


Link to post
Share on other sites

Hi Dean!

Thanks for providing this valuable information.  It's information that should be useful, I think, especially to some of our newbies. 

A very rough summary:  Anabolic drugs build muscles, and shorten expected lifespan.  This includes GH, IGF1 and testosterone.

(Happily, I've never heard of anyone trying to supplement IGF1.)

  --  Saul

Share this post


Link to post
Share on other sites

Saul,

1 hour ago, Saul said:

(Happily, I've never heard of anyone trying to supplement IGF1.)

While banned by bodybuilding and sports organizations, attempting to boost IGF-1 via supplements is not that unusual among bodybuilders and professional athletes:

https://nyti.ms/Wwy4mf

--Dean

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×