Low Testosterone via CR - Good or Bad?

Dean Pomerleau · December 29, 2015

Low testosterone (hypogonadism), besides potentially reducing quality of life (a commonly held notion the validity of which many of us male CR folks would contend...), has been thought to be potentially associated with increased mortality, particularly from cardiovascular disease, at least among the general (non-CR) population. Here again is a situation where we hope that our low testosterone (as frequently but not universally experienced by CR men) has different health/longevity implications than hypogonadism in the general population, where it is frequently associated with obesity and other indicators of ill-health.

Well, this study posted by Al Pater (thanks Al!) from the Framingham Heart Study may help ease those doubts and concerns. It found that even in a general population of 254 elderly men (avg age 75), neither low testosterone nor absolute level or change in other sex hormones were associated with increased mortality at either 5 or 10 year follow-up, once other confounding factors were statistically factored out. The confounders they corrected for were age, body mass index, smoking, total cholesterol, high-density lipoprotein cholesterol, type 2 diabetes, systolic blood pressure, and antihypertensive medication - all of which seem reasonable to factor out.

To quote from the discussion of the free full text:

Leveraging the unique data set and design of the community-based FHS, the present study is

the first to investigate longitudinal trajectory patterns of serial sex steroid and gonadotropins

measurements and their associations with 5-year and 10-year risk of incident clinical CVD

and all-cause mortality. We observed no consistent association of sex steroids,

gonadotropins, and their trajectories with incident clinical CVD or all-cause mortality risk in

254 elderly men in the community.

In other words, it appears that if you are a healthy elderly man (i.e. without the confounders listed above, which hopefully most CR folks do/will avoid), having low testosterone is not associated with an increased risk of cardiovascular disease or overall mortality. So we've got that goin' for us...

--Dean

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[1] Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study.

Haring R, Teng Z, Xanthakis V, Coviello A, Sullivan L, Bhasin S, Murabito JM, Wallaschofski H, Vasan RS.

Clin Endocrinol (Oxf). 2013 Apr;78(4):629-34. doi: 10.1111/cen.12013.

PMID: 22901104 Free PMC Article

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161203/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161203/pdf/nihms622794.pdf

Abstract

BACKGROUND:

Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date.

METHODS:

We prospectively evaluated 254 elderly men (mean age, 75·5 years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5- and 10-year follow-up.

RESULTS:

We observed no association between baseline concentrations of sex steroids, gonadotrophins and their trajectories with incident clinical CVD over 5- and 10-year follow-up. Although higher baseline TT concentrations were associated with lower mortality risk at 5 years (hazard ratio per quartile increment, 0·74; 95% confidence interval, 0·56-0·98), correction for multiple statistical testing (P < 0·005) rendered this association statistically nonsignificant. Repeat analyses at the 10-year follow-up time point also demonstrated no significant association between sex steroids, gonadotrophins or their trajectories and mortality.

CONCLUSION:

Investigating longitudinal trajectory patterns of serial sex steroid and gonadotrophin measurements, the present study found no consistent associations with incident clinical CVD and all-cause mortality risk in elderly men from the community.

Zeta · January 2, 2016

Thanks for this, Dean. I concluded the same thing after a review of the literature a while back: low testosterone, even below the ref. range, isn't likely a problem for a healthy CR practitioner. It might even be protective, in general, or part of the mechanism by which CR works (via AMPK signaling, for ex.)

Zeta

AlPater · January 2, 2016

Aging and caloric restriction: effects on Leydig cell steroidogenesis.

Chen H, Luo L, Liu J, Brown T, Zirkin BR.

Exp Gerontol. 2005 Jun;40(6):498-505.

PMID: 15935587

http://www.sciencedirect.com.sci-hub.io/science/article/pii/S0531556505000628

Abstract

We have shown previously that testosterone concentration in the blood serum of Brown Norway rat becomes reduced with aging, and that this results from reduced testosterone production by individual Leydig cells. Herein we examine the effects of caloric restriction (CR), an intervention shown to delay or inhibit age-associated pathologic and biologic changes in a number of systems and organisms, on Leydig cell steroidogenic function. CR (40%) was initiated in 4 month-old Brown Norway rats, and continued through age 34 months. Serum testosterone concentration in the ad libitum (AL)-fed controls was reduced by 30% from 5 to 13 months, by another 67% through 25 months, and then was sustained through 34 months. For the CR rats, the serum testosterone level was reduced to 45% of AL controls by 5 months, only 6 weeks after the initiation of the CR regimen. There was no further reduction through 25 months, at which time serum testosterone concentration in CR animals was significantly higher than in AL controls. By age 28-34 months, there was no significant difference between the two diets. The weights of prostate and seminal vesicle, two biomarkers of serum androgen levels, were consistent with the changes in serum testosterone concentration in both AL and CR animals. The ability of isolated Leydig cells to produce testosterone in vitro also paralleled the age- and CR-related changes in serum testosterone concentration. CR resulted in a rapid, 36% reduction in testosterone production from control by age 5 months. In contrast to cells from the AL rats, there were no further decreases in testosterone production through age 25 months. Indeed, Leydig cells from the 25 month-old CR rats produced significantly greater amounts of testosterone than cells from the 25 month-old AL rats. These results indicate that short-term CR results in the suppression of Leydig cell function and in reduction in serum testosterone levels. The significantly higher concentrations of serum testosterone concentration, and increased Leydig cell testosterone production, elicited by CR in 25 month-old rats compared to AL controls suggest that long-term CR can transiently suppress the reductions in steroidogenesis that are characteristic of aging.

AlPater · January 2, 2016

Below are my data for testosterone showing, I think, that as I aged, my levels relative to reference ranges fluctuating with the age that I was and the labs testing me, increased with age. CR preserved my testosterone levels that were initially way below the reference ranges at younger CRed ages.

First, is my Free Testosterone, reference range 31-163 nM, values chronologically.

1995 = 16.5 7.9 9.1 2.7 (I had pneuomonia) 10.6 ~10 11.1 March 2002 = 5.8

Then comes my reverse chronological later values.

Test 22/01/14 May 26/11 May 20/10 Nov. 20/08 Sept 13/07 Apr 10/06 Ref. Unit

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

Testosterone 18.2 (8.4-28.8) July 5/12 A 9.0 (10.0-30.0 nmol/L) May 26/11 16.0 (9.9-27.8 nm) May 20/10 10.7 (9.9-27.8 nm) 14.9 (9.9-22.8 nM) Feb 11, 2009 11.29 on 8/21/07 (6.1-27.1 nM) 5.8 in ?/03/2002 (31-163 nm) 9.1 in 1/6/97 (31-163 nM)

Dean Pomerleau · January 26, 2016

All,

I'm changing the title of this thread from "Low Testosterone May Not Be So Bad" to "Low Testosterone via CR - Good or Bad?" as a result of this new paper [1] posted by Al Pater (thanks Al!).

In the study, researchers cut the cahones off of unfortunate lean or obese male rats to eliminate testosterone (T), and then tested a variety of things, most importantly brain health, both physiologically (via hippocampal synaptic plasticity) and behaviorally (via Morris water maze test).

Unfortunately (at least for low-T CRers like me), the results were somewhat troubling.

In particular, after 8 weeks, the lean rats with low T exhibited a reduction in synaptic plasticity and impaired water maze performance compared with lean control rats. Below is the graph for the water maze test - where there is a submerged platform somewhere in the tank that the rats have to learn to find and climb up on to avoid the unpleasant water (see embedded video at bottom for mouse learning water maze - skip to 1:30 to see him succeed!). Here is the key for the different groups: control-lean rats (NDS), ORX-lean rats (NDO), control-obese rats (HFS) and ORX-obese rats (HFO).

As you can see, the lean orchiectomized rats (NDO group) spent less time in the part of the tank with the platform at 8 and 12 weeks, and were slower to learn to climb up on the platform at 12 weeks. than controls. This is widely interpreted to be the rat-equivalent of cognitive impairment.

Here is the brain data - in the form of graphs of synapse spine density in the hippocampus.

At 4-weeks (top graph) the lean orchiectomized (NDO) group has just as many dentritic spines as the lean control (NDS) group. But at 8-weeks (middle graph) and 12-weeks (bottom graph), the NDO group's dendritic spine count was significantly lower.than controls.

In fact, by both these metrics (water maze and hippocampus synapse count), it didn't matter whether the rats were lean or obese (HFO) - their brain health appeared to be similarly impaired by loss of testosterone.

Of course, without testes, these rats had very low testosterone - so (besides the fact they were rats and not humans), there may be reason to discount these findings of impaired cognition as a result of low testosterone, since we CR human men have less, but not insignificant testosterone levels. At the same time though, given this uncertainty, it is probably wise for male CRers to take extra care to preserve brain health. Here are a few possible avenues for doing that (with some obviously more proven than others, before Michael jumps down my throat... :)xyz ) - exercise, creative hobbies, diet (fruits/veggies - although surprisingly weak benefit, nuts/EVOO), sleeping on your side, DHA + B vitamins, curcumin, natto, and good old CR.

--Dean

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[1] Metabolism. 2016 Feb;65(2):54-67. doi: 10.1016/j.metabol.2015.10.015. Epub 2015 Oct 22.

Testosterone deprivation has neither additive nor synergistic effects with obesity on the cognitive impairment in orchiectomized and/or obese male rats.

Pintana H, Pratchayasakul W, Sa-Nguanmoo P, Pongkan W, Tawinvisan R, Chattipakorn N, Chattipakorn SC.

PMID: 26773929

Full text: http://www.sciencedirect.com.sci-hub.io/science/article/pii/S0026049515003078

Abstract

OBJECTIVE:

Previous studies demonstrated a correlation between cognitive decline and either testosterone deprivation or obesity. However, the effect of obesity combined with testosterone deprivation on cognitive function has not been investigated. This study investigated the effects of obesity on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in testosterone-deprived male rats.

MATERIALS/METHODS:

Male Wistar rats were divided into sham-operated (control) and bilateral orchiectomized (ORX) groups. Rats in each group were further divided into two subgroups to receive either a normal diet (ND) or a high fat diet (HFD) for 4, 8 or 12weeks. Blood samples were collected to determine metabolic parameters. Cognitive function was tested using the Morris Water Maze Test. At the end of the study, brains were removed to investigate brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity.

RESULTS:

Both control-obese and ORX-obese rats developed peripheral insulin resistance at week eight, and brain insulin resistance as well as brain mitochondrial dysfunction at week 12. However, the ORX-obese rats developed cognitive impairment and decreased hippocampal synaptic plasticity beginning at week eight, whereas the control-obese rats developed these impairments later at week 12. Although both peripheral and brain insulin resistance were not observed in both the control-lean and ORX-lean rats, impaired cognition and decreased hippocampal synaptic plasticity were found in the ORX-lean rats beginning at week eight.

CONCLUSION:

These findings suggest that testosterone deprivation has neither additive nor synergistic effects over obesity in the development of cognitive dysfunction in orchiectomized-obese male rats.

KEYWORDS:

Brain insulin sensitivity; Brain mitochondrial function; Hippocampal synaptic function; Obese-insulin resistance; Testosterone deprivation

Dean Pomerleau · February 26, 2016

All,

Testosterone replacement has been in the news quite a bit lately. Last week we saw the results of a double-blind testosterone replacement therapy study [2] of 800 men over age 65, which found men's self-reported level of sexual activity and performance improved in the treatment group relative to placebo, but their walking speed and overall vitality saw little if any improvement. And on the distinctly negative side, this new study [3] found that testosterone replacement therapy may increase blood clotting and bone necrosis, resulting in even more plaintiffs in class action lawsuits against the makers of testosterone gel.

So it appears even more ill-advised to go the route of testosterone replacement therapy to counteract that low testosterone that often accompanies CR.

But what about the potential for impaired cognitive function resulting from low testosterone, as evidenced by PMID 26773929 discussed in the immediately preceding post? Well, it's unfortunate that testosterone replacement therapy appears to be ill-advised, since the same authors who showed in PMID 26773929 that cognition was impaired by castration in lean rats have found in this new study [1] that testosterone replacement reversed those detrimental cognitive effects of castration:

In [lean, castrated] rats, testosterone [replacement] decreased circulation and brain oxidative stress levels, attenuated brain

mitochondrial ROS production, and restored hippocampal synaptic plasticity as well as cognitive function.

So low testosterone may be bad for brain health, but testosterone replacement therapy doesn't seem like an appealing option in humans due to its other detrimental effects. :-(

--Dean

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[1] Age (Dordr). 2015 Oct;37(5):84. doi: 10.1007/s11357-015-9827-4. Epub 2015 Aug 16.

Testosterone replacement attenuates cognitive decline in
testosterone-deprived lean rats, but not in obese rats, by mitigating brain
oxidative stress.

Pintana H, Pongkan W, Pratchayasakul W, Chattipakorn N, Chattipakorn SC.

Full text: http://sci-hub.io/10.1007/s11357-015-9827-4

Abstract

Testosterone replacement improves metabolic parameters and cognitive
function in hypogonadism. However, the effects of testosterone therapy on
cognition in obese condition with testosterone deprivation have not been
investigated. We hypothesized that testosterone replacement improves
cognitive function in testosterone-deprived obese rats by restoring brain
insulin sensitivity, brain mitochondrial function, and hippocampal synaptic
plasticity. Thirty male Wistar rats had either a bilateral orchiectomy (ORX:
O, n = 24) or a sham operation (S, n = 6). ORX rats were further divided
into two groups fed with either a normal diet (NDO) or a high-fat diet (HFO)
for 12 weeks. Then, ORX rats in each dietary group were divided into two
subgroups (n = 6/subgroup) and were given either castor oil or testosterone
(2 mg/kg/day, s.c.) for 4 weeks. At the end of this protocol, cognitive
function, metabolic parameters, brain insulin sensitivity, hippocampal
synaptic plasticity, and brain mitochondrial function were determined. We
found that testosterone replacement increased peripheral insulin
sensitivity, decreased circulation and brain oxidative stress levels, and
attenuated brain mitochondrial ROS production in HFO rats. However,
testosterone failed to restore hippocampal synaptic plasticity and cognitive
function in HFO rats. In contrast, in NDO rats, testosterone decreased
circulation and brain oxidative stress levels, attenuated brain
mitochondrial ROS production, and restored hippocampal synaptic plasticity
as well as cognitive function. These findings suggest that testosterone
replacement improved peripheral insulin sensitivity and decreased oxidative
stress levels, but failed to restore hippocampal synaptic plasticity and
cognitive function in testosterone-deprived obese rats. However, it provided
beneficial effects in reversing cognitive impairment in
testosterone-deprived non-obese rats.

PMID: 26277724

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

[2] N Engl J Med. 2016 Feb 18;374(7):611-24. doi: 10.1056/NEJMoa1506119.

Effects of Testosterone Treatment in Older Men.

Snyder PJ(1), Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley

JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar

JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D,

Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER

3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS;

Free full text: http://www.nejm.org/doi/full/10.1056/NEJMoa1506119

BACKGROUND: Serum testosterone concentrations decrease as men age, but benefits

of raising testosterone levels in older men have not been established.

METHODS: We assigned 790 men 65 years of age or older with a serum testosterone

concentration of less than 275 ng per deciliter and symptoms suggesting

hypoandrogenism to receive either testosterone gel or placebo gel for 1 year.

Each man participated in one or more of three trials--the Sexual Function Trial,

the Physical Function Trial, and the Vitality Trial. The primary outcome of each

of the individual trials was also evaluated in all participants.

RESULTS: Testosterone treatment increased serum testosterone levels to the

mid-normal range for men 19 to 40 years of age. The increase in testosterone

levels was associated with significantly increased sexual activity, as assessed

by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly

increased sexual desire and erectile function. The percentage of men who had an

increase of at least 50 m in the 6-minute walking distance did not differ

significantly between the two study groups in the Physical Function Trial but did

differ significantly when men in all three trials were included (20.5% of men who

received testosterone vs. 12.6% of men who received placebo, P=0.003).

Testosterone had no significant benefit with respect to vitality, as assessed by

the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who

received testosterone reported slightly better mood and lower severity of

depressive symptoms than those who received placebo. The rates of adverse events

were similar in the two groups.

CONCLUSIONS: In symptomatic men 65 years of age or older, raising testosterone

concentrations for 1 year from moderately low to the mid-normal range for men 19

to 40 years of age had a moderate benefit with respect to sexual function and

some benefit with respect to mood and depressive symptoms but no benefit with

respect to vitality or walking distance. The number of participants was too few

to draw conclusions about the risks of testosterone treatment. (Funded by the

National Institutes of Health and others; ClinicalTrials.gov number,

NCT00799617.).

PMID: 26886521

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[3] Orthopedics. 2015 Dec 1;38(12):e1073-8. doi: 10.3928/01477447-20151120-03.

Testosterone Therapy Can Interact With Thrombophilia, Leading to Osteonecrosis.

Glueck CJ, Riaz R, Prince M, Freiberg RA, Wang P.

Free full text: http://www.healio.com/orthopedics/journals/ortho/2015-12-38-12/%7Bf522e3c6-5106-4e7f-bc79-73d2a0a97b31%7D/testosterone-therapy-can-interact-with-thrombophilia-leading-to-osteonecrosis

Although this effect is not widely recognized, testosterone therapy can interact
with thrombophilia, causing osteonecrosis. In 12 men and 4 women who had
idiopathic osteonecrosis a median of 6 months after the onset of testosterone
therapy, the authors examined the interaction between testosterone therapy and
previously undiagnosed thrombophilia. The authors hypothesized that patients who
had osteonecrosis after starting testosterone therapy were more likely than 110
normal control subjects or 48 patients who had osteonecrosis and were not
receiving testosterone therapy to have thrombophilia. Measures of thrombophilia
included Factor V Leiden, prothrombin, PAI-1 gene mutations, Factor VIII, Factor
XI, anticardiolipin antibody immunoglobulin G or immunoglobulin M, and
homocysteine values. In 10 cases, osteonecrosis occurred 6 months or less after
the onset of testosterone therapy, and in all 16 cases, it occurred after a
median of 6 months of testosterone therapy. Of the 16 cases, 5 (31%) were Factor
V Leiden heterozygotes vs 2 of 109 (2%) healthy control subjects (P=.0003) and 4
of 48 patients who had osteonecrosis and were not receiving testosterone therapy
(P=.04). Of the 16 cases, 4 (25%) had high (>150%) Factor VIII levels vs 7 of 103
(7%) healthy control subjects (P=.04), and 3 (19%) had high (>150%) Factor XI
levels vs 3 of 101 (3%) healthy control subjects (P=.03). Of the 16 patients with
osteonecrosis, 14 (88%) had at least 1 abnormal procoagulant value (of the 8
measured) vs 47 of 110 (43%) healthy control subjects (P=.0009). Of the 5 men
whose serum estradiol level was measured while they were receiving testosterone
therapy, this level was high (≥42.6 pg/mL) in 4. When testosterone therapy is
given to patients with thrombophilia, they are at increased risk for
osteonecrosis. [Orthopedics. 2015; 38(12):e1073-e1078.].

Copyright 2015, SLACK Incorporated.

PMID: 26652327

drewab · March 4, 2016

I think there is something missing from the discussion of testosterone, CR, and cognition here. Having been on a wfpb [author probably means: whole-food, plant-based. -Moderator.], mildly CR'd lifestyle for 5 years this month, my anecdotal experience is that my cognition has improved drastically. I used to find work overwhelming at times, struggle to make decisions, have challenges learning new things, and so on. Today I find many of the previous work challenges I've experienced to be significantly less. Of course to some extent they are present - I am still human after all.

This really brings up more questions than answers, but some possible trajectories are this:

1) Low T accompanied by CR is actually beneficial, for reasons we don't understand

2) Low T is harmful on cognition, but the net benefit from CR overcomes this and results in a positive effect on cognition, due to other mechanisms. (speculating increased BDNF, increased dopamine, etc.)

3) There is something we don't fully understand here which makes all of the current data a wash

4) Some other pathway is activated through exercise, meditation, low glucose, specific phytonutrients of foods (think greens, berries, etc.).

So while the relationship is extremely difficult to tease out, my personal n=1 experiment has indicated that a CR lifestyle benefits cognition greatly.

One study I would love to see is a group of CR followers on TRT for a couple of decades compared to a control without TRT. Such a study is damn near impossible to happen though.

Todd Allen · June 10, 2016

Is there any study to correlate levels of CR with testosterone?

I recently began an aggressive diet hoping to radically drop my testosterone as I have a progressive neuro-muscular disease, SBMA, and the rate of progression is directly dependent on testosterone level. I went from roughly 2500 calories/day to 1000 calories/day for a week and after reading many things suggesting that could be too extreme have backed off to about 1200 calories/day. Each day my health seems to be improving and I'm feeling better for a wide variety of reasons, but I'm also feeling friskier while I was hoping for a loss of sex drive. I hope those subjective feelings are due to other effects and not increasing testosterone...

Dean Pomerleau · June 10, 2016

Todd A.,

Welcome to the CR Society Forums!

Sorry about your health challenges, but you've come to the right place to ask about CR.

Is there any study to correlate levels of CR with testosterone?

Yes and no. Chronic CR usually reduces testosterone, and importantly for you free testosterone [1], and (more controversially) libido in most (but not all) adult men. But I don't know of any dose/response data on how (or even if) degree of CR correlates with magnitude of testosterone drop. But I will note that none of the men (including me) in [1] were nearly as CRed as you indicate that you are (see below).

But perhaps as significantly for you, CR not only reduces free & total testosterone, it also activates SIRT1, which appears beneficial for spinal and bulbar muscular atrophy (SBMA) [2] through the deacetylation of androgen receptors (ARs),. Deacetylation of your ARs deactivates them, which in your case is a good thing since your ARs are mutated and therefore apparently deleterious for cells in your motor cortex when bound with testosterone. But maybe you already knew that, and that's why you're here...

I recently began an aggressive diet hoping to radically drop my testosterone as I have a progressive neuro-muscular disease, SBMA, and the rate of progression is directly dependent on testosterone level. I went from roughly 2500 calories/day to 1000 calories/day for a week and after reading many things suggesting that could be too extreme have backed off to about 1200 calories/day. Each day my health seems to be improving and I'm feeling better for a wide variety of reasons, but I'm also feeling friskier while I was hoping for a loss of sex drive. I hope those subjective feelings are due to other effects and not increasing testosterone...

My suggestion is to give it time. You haven't shared your starting point (age, BMI, etc), but unless you're naturally very thin with little body fat, you've probably got plenty of metabolic reserves, so you're body may not yet realize how much of a calorie deficit you are running. This can definitely result in an "buzz" in the early days of CR that many of us experience. If you can deal with the hunger, it can feel pretty good on the way down. BTW, 1200kcal/day is almost certainly not sustainable in the long run, and could lead to rapid muscle catabolism, especially if your condition is such that it makes it hard for you to exercise. Given that SBMA is associated with degeneration of certain skeletal muscles already, extreme CR (like 1200kcal/day for a man) could make matters worse. So if I were you I wouldn't cut calories nearly as drastically as you appear to be doing.

One other caveat. Another consistent and major effect of CR is to reduce Insulin Like Growth Factor 1 (IGF-1). Although it is not without controversy, this effect is generally thought to be beneficial in healthy people, since IGF-1 is an anabolic hormone associated with the promotion of cancer grown and possibly accelerated aging. But in your case, anabolic hormones besides testosterone, and in particularly IGF-1, are potentially beneficial, both for maintaining motor neurons and muscle cells generally, and specifically by inhibiting your messed up ARs. From review article [3]:

The neurodegenerative disease SBMA is caused by expansion of a CAG repeat encoding polyglutamine in the androgen receptor (AR) gene, resulting in accumulation of AR and loss of motor neurons in the brainstem and spinal cord. Augmentation of IGF-I levels in the muscle increases AR clearance through the ubiquitin-proteasome system and AR phosphorylation by Akt [4], and in a mouse model of SBMA, muscle-specific overexpression of IGF-I was able to improve motor performance and body weight [4]. Collectively, these data suggest that IGF-I has a direct inhibitory effect on mutant AR, which might help prevent motor neuron degeneration in SBMA.

So while CR-induced reduction in free testosterone may be good in your case, CR-induced reduction in IGF-1 may be bad.

Finally, it goes without saying this should not be interpreted as medical advice. I'm just some random guy on the internet trying to help, without medical training and without any knowledge about your specific situation. I also have only the cursory understanding of your disease and the potential impact CR might have on it that an hour of targeted internet searching and reading can provide. Heck, up until a couple hours ago I'd never even heard of SBMA. In short, don't listen to me. Talk to your doctor(s) if you haven't already about whether CR makes sense for your condition and your situation. By all means bring printouts of these abstracts/papers, and if he/she dismisses the idea of CR out of hand, look for another specialist who will at least give it careful consideration before advising for or against it. BTW, this blog looks like a pretty good resource for Kennedy's disease (aka SBMA) sufferers, if you haven't found it already.

Good luck and all the best. Please keep us updated on what you decide in consultation with your doc, and how it works out.

--Dean

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[1] Aging Cell. 2010 Apr;9(2):236-42. doi: 10.1111/j.1474-9726.2010.00553.x. Epub

2010 Jan 20.

Long-term effects of calorie restriction on serum sex-hormone concentrations in

men.

Cangemi R(1), Friedmann AJ, Holloszy JO, Fontana L.

Author information:

(1)Center for Human Nutrition, Washington University School of Medicine, St.

Louis, MO, USA.

Calorie restriction (CR) slows aging and consistently reduces circulating sex

hormones in laboratory animals. However, nothing is known regarding the long-term

effects of CR with adequate nutrition on serum sex-hormone concentration in lean

healthy humans. In this study, we measured body composition, and serum total

testosterone, total 17-beta-estradiol, sex hormone-binding globulin (SHBG), and

dehydroepiandrosterone sulfate (DHEA-S) concentrations in 24 men (mean age 51.5

+/- 13 years), who had been practicing CR with adequate nutrition for an average

of 7.4 +/- 4.5 years, in 24 age- and body fat-matched endurance runners (EX), and

24 age-matched sedentary controls eating Western diets (WD). We found that both

the CR and EX volunteers had significantly lower body fat than the WD volunteers

(total body fat, 8.7 +/- 4.2%; 10.5 +/- 4.4%; 23.2 +/- 6.1%, respectively; P =

0.0001). Serum total testosterone and the free androgen index were significantly

lower, and SHBG was higher in the CR group than in the EX and WD groups (P < or =

0.001). Serum 17beta-estradiol and the estradiol:SHBG ratio were both

significantly lower in the CR and EX groups than in the WD group (P < or =

0.005). Serum DHEA-S concentrations were not different between the three groups.

These findings demonstrate that, as in long-lived CR rodents, long-term severe CR

reduces serum total and free testosterone and increases SHBG concentrations in

humans, independently of adiposity. More studies are needed to understand the

role of this CR-mediated reduction in sex hormones in modulating the pathogenesis

of age-associated chronic diseases such as cancer and the aging process itself.

PMCID: PMC3569090

PMID: 20096034

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

[2] J Neurosci. 2011 Nov 30;31(48):17425-36. doi: 10.1523/JNEUROSCI.3958-11.2011.

SIRT1 modulates aggregation and toxicity through deacetylation of the androgen

receptor in cell models of SBMA.

Montie HL(1), Pestell RG, Merry DE.

Author information:

(1)Department of Biochemistry and Molecular Biology, Thomas Jefferson University,

Philadelphia, Pennsylvania 19107, USA.

Posttranslational protein modifications can play a major role in disease

pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity

of a variety of proteotoxic proteins. The androgen receptor (AR) is substantially

modified, in response to hormone binding, by phosphorylation, sumoylation, and

acetylation; these modifications might thus contribute to DHT-dependent

polyglutamine (polyQ)-expanded AR proteotoxicity in spinal and bulbar muscular

atrophy (SBMA). SIRT1, a nuclear protein and deacetylase of the AR, is

neuroprotective in many neurodegenerative disease models. Our studies reveal that

SIRT1 also offers protection against polyQ-expanded AR by deacetylating the AR at

lysines 630/632/633. This finding suggested that nuclear AR acetylation plays a

role in the aberrant metabolism and toxicity of polyQ-expanded AR. Subsequent

studies revealed that the polyQ-expanded AR is hyperacetylated and that

pharmacologic reduction of acetylation reduces mutant AR aggregation. Moreover,

genetic mutation to inhibit polyQ-expanded AR acetylation of lysines 630/632/633

substantially decreased its aggregation and completely abrogated its toxicity in

cell lines and motor neurons. Our studies also reveal one means by which the AR

acetylation state likely modifies polyQ-expanded AR metabolism and toxicity,

through its effect on DHT-dependent AR stabilization. Overall, our findings

reveal a neuroprotective function of SIRT1 that operates through its

deacetylation of polyQ-expanded AR and highlight the potential of both SIRT1 and

AR acetylation as powerful therapeutic targets in SBMA.

PMID: 22131404

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

[3]

Trends Endocrinol Metab. 2013 Jun;24(6):310-9. doi: 10.1016/j.tem.2013.03.004.
Epub 2013 Apr 27.

The therapeutic potential of IGF-I in skeletal muscle repair.

Song YH(1), Song JL, Delafontaine P, Godard MP.

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732824/

Skeletal muscle loss due to aging, motor-neuron degeneration, cancer, heart
failure, and ischemia is a serious condition for which currently there is no
effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role
in muscle maintenance and repair. Preclinical studies have shown that IGF-I is
involved in increasing muscle mass and strength, reducing degeneration,
inhibiting the prolonged and excessive inflammatory process due to toxin injury,
and increasing the proliferation potential of satellite cells. However, clinical
trials have not been successful due to ineffective delivery methods. Choosing the
appropriate isoforms or peptides and developing targeted delivery techniques can
resolve this issue. Here we discuss the latest development in the field with
special emphasis on novel therapeutic approaches.

Copyright © 2013 Elsevier Ltd. All rights reserved.

PMCID: PMC3732824
PMID: 23628587

-----------

[4] Neuron. 2009 Aug 13;63(3):316-28. doi: 10.1016/j.neuron.2009.07.019.

Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal

and bulbar muscular atrophy.

Palazzolo I(1), Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor

JP, Sumner CJ, Fischbeck KH, Pennuto M.

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735765/

Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal

and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated

phosphorylation of AR reduces ligand binding and attenuates the mutant AR

toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1)

reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome

system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice

overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle

show evidence of increased Akt activation and AR phosphorylation and decreased AR

aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and

histopathological abnormalities, extends the life span, and reduces both muscle

and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated

inactivation of mutant AR as a strategy to counteract disease in vivo and

demonstrates that skeletal muscle is a viable target tissue for therapeutic

intervention in SBMA.

PMCID: PMC2735765

PMID: 19679072

drewab · June 10, 2016

Here is an interesting study on caloric timing and testosterone. It's interesting because subjects were lean and on a low calorie diet. What's interesting is that in the group eating a big breakfast (despite keeping total calories the same) free testosterone dropped 50% (and SHBG increased 105%). The unfortunate limit of this study is that it's on women, who have PCOS. So it really may not be all that useful. Most of us here are men, let alone members of a gender who can't develop PCOS.

What's interesting is the subjects BMI is low enough and they were fed low-calories.

Click here for the full text.

Abstract

In women with PCOS (polycystic ovary syndrome), hyperinsulinaemia stimulates ovarian cytochrome P450c17α activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOSwomen. A total of 60 lean PCOS women [bMI (body mass index), 23.7±0.2 kg/m²] were randomized into two isocaloric (~1800 kcal; where 1 kcal≈4.184 J) maintenance diets with different meal timing distribution: a BF (breakfast diet) (980 kcal breakfast, 640 kcal lunch and 190 kcal dinner) or a D (dinner diet) group (190 kcal breakfast, 640 kcal lunch and 980 kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUC(glucose) (glucose area under the curve) and AUC(insulin) (insulin area under the curve) by 7 and 54% respectively. In the BF group, free testosterone decreased by 50% and SHBG (sex hormone-binding globulin) increased by 105%. GnRH (gonadotropin-releasing hormone)-stimulated peak serum 17OHP (17α-hydroxyprogesterone) decreased by 39%. No change in these parameters was observed in the D group. In addition, women in the BF group had an increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17α activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS. PMID: 23688334

Todd Allen · June 11, 2016

Dean, I'm impressed with your research skills and level of comprehension jumping in on something new. Yes, I was aware of the SIRT1 connection, the possibility for IGF reduction which might be a problem and several other things, but I've been following the research on my disease for decades, though only recently did I discover sci-hub where I could read full articles instead of just abstracts. And I finally came to realize that most of the targets for therapeutic intervention for SBMA being studied (and many other progressive diseases) are part of metabolic pathways which degrade with aging. Eventually there will be a fantastically expensive therapeutic drug that up regulates one or more of those factors and provides some relief, but the process is grindingly slow.

I've seen many doctors but no one ever told me there is a known intervention with the potential to improve almost all of the investigated therapeutic targets for SBMA besides IGF and that it is caloric restriction. Reading up on caloric restriction brought me here. I browsed a couple other places devoted to CR but this one is the most science minded I've found. BTW, I've read many people who practice CR also reduce protein and it appears that has a bigger impact on IGF than reducing carbohydrates. I'm not aiming for the full range of longevity benefits that protein reduction might bring. I'm just hoping to get my disease issues under control.

When I last saw my neurologist and rheumatologist I told them I was contemplating nicotinamide riboside and caloric restriction as possible approaches to slow my condition and hopefully buy more time to wait for a treatment to be approved. Neither was enthusiastic but they agreed it would be benign so long as I didn't over do it. I had no confidence I had capacity to over do it and didn't press for any details on what would be considered over doing it.

I'm 51, 5' 10", 163 lbs, and losing 2-3 lbs / week down from a peak of 173 lbs. I didn't track how many calories I was eating before starting to diet but I guess it was about 2500 / day. My caloric intake has been falling fast the past few years as I've become increasingly disabled but not fast enough to prevent weight gain as my activity level plummeted faster. My BMI isn't awful, but I've lost a lot of muscle and it's only recently sunk in that I've become quite obese. I expect I have more than 30 lbs of fat to yet lose, or at least 3 more months at my current pace.

For most of my life I weighed between 160 and 165 lbs. For a couple years starting when I was 19 I tried hard and managed to get my weight up to 175 lbs while doing intensive body building with a group of friends but it became obvious something wasn't right and that's when I became fairly certain I had inherited my grandfather's disease. When I stopped trying to build muscle my weight rapidly returned to my normal range. In addition to SBMA, I believe I have another inherited trait that I haven't found named or associated with a gene. It is an overly responsive trigger of fight/flight response which appears in blood and 24 hour urine tests as quite elevated norepinephrine levels. Which got me subjected to more tests looking for a pheochromacytoma that I was pretty sure wasn't there, but my doctors insisted on ruling out.

Most of my life I've eaten without restraint, a carbohydrate junkie, but I didn't gain weight. I've never dieted and hardly considered dieting. Having a meal delayed made me prone to fainting and could put me into a panic. I have some symptoms typical of diabetes, such as periods of ridiculously high urine production, strong blood sugar swings, erratic blood pressure with a tendency to significant hypertension, etc. But repeated testing showed no insulin insensitivity. I've always carried a bag of calorie rich foods and often a bottle of orange juice (thought it was healthy...) with me whenever leaving home or my office and always insisted on having a refrigerator in my office where ever I've worked so I could stave off trouble whenever I felt I was crashing.

The endocrine abnormality had positive aspects when I was young, despite being small and clumsy I rarely lost fights and I used to think not needing sleep in times of stress was handy, but as I've gotten older I believe it has augmented the effects of my neuro-muscular disorder. SBMA is considered primarily a motor neuron and skeletal muscle disease, but in my case I've developed sensory neuropathy and autonomic nervous system dysfunction resulting in quite a few more issues such as Raynaud's syndrome, digestive issues, etc. and in the last couple years increasing memory issues too.

I knew I should take control of my diet but just contemplating it would begin to provoke my panic response. I looked for other options but the best I could find was a supplement, nicotinamide riboside, a NAD precursor that might promote SIRT1 activation. The lax regulation of supplements and the limited amount of peer reviewed data made me hesitant but it seemed fairly safe and dirt cheap compared to many prescription medications so I started taking it at the standard dose of 125 mg twice daily. After 2 weeks without any noticeable effects positive or negative, I mustered the resolve to attempt dieting. I fully expected failure and came close to giving up on the second day. But then it got much easier and its been shockingly effective, especially in the last couple weeks.

All of my lesser health issues, insomnia, digestive trouble, blood pressure, blood sugar swings, chronic pains and especially my mood have been improving at a rate I would never have dreamed possible. Even things I thought were gone like my balance and the ability to walk unassisted started coming back. A week ago I got on a bicycle for the first time in 2 years. I managed to ride a couple hundred feet at a walking pace but got so weak I nearly crashed. But each day has gotten better. This morning I rode 4 miles in 45 minutes. Pathetic, but thrilling for me as I doubted I would ever ride my bikes again and thought I should start getting rid of them. I've got hang gliders collecting dust for much longer and I'd stick to any amount of calorie restriction if I could fly again.

For my diet, I eliminated all concentrated carbs, which is mostly what I was eating previously. I went cold turkey on fruit juices, bread, potatoes, pasta, rice, chips, cereals, sweets and everything with added sugar. The only processed foods I've been eating are mustard and pickles. My wife and I have a large garden and a flock of 9 hens, and I greatly upped my intake of garden vegetables. Most days for protein I've been eating 3 eggs, a couple ounces of lean pasture raised beef and a quarter cup of cottage cheese. Without the carbs I was eating about 1000 calories per day for a week but read that was too extreme and likely to quickly result in problems so I upped it to roughly 1200 with the addition of a few bites of fruit and an ounce of mixed tree nuts. I haven't made any attempt at true accuracy since my caloric target is rather arbitrary, I don't weigh anything and just use rough figures for calories looked up on the internet, such as 75 calories per egg. I eat two roughly equal meals a day without snacking.

My confidence has been growing that I can sustain eating whatever I decide is appropriate. At least if I can stay in ketosis. I don't know if it is possible to remain indefinitely in ketosis but I think it works much better for me than glycolysis. I started out at an aggressive pace because I didn't expect any significant results for a long time and hoped that losing a few pounds as quick as possible would bring little gains like being able to get back up again after a fall, enough of a reward to keep me going until other improvements might manifest.

I'm fairly clueless as to what is the most appropriate rate to do this. The gains have been making me euphorically greedy wanting to push it ever faster and instead of struggling not to eat I have been telling myself it's dangerous not to eat. Sometimes I miss one of my two daily meals and I make up for it by eating a carrot or a pickle, telling myself I can add more to the next cooked meal but when that time rolls around I talk myself out of making up the skipped food since nothing bad has happened so far. I'm increasingly certain I should stay on a calorie restricted diet for the rest of my life. But I don't know what level of restriction will optimize the rewards with respect to the risks. And I don't know if I should switch to a more long term sustainable level now. My desire is to keep it aggressive until I've lost a significant percentage of my body fat and then ease back to a long term target. I have another visit with my rheumatologist in about a month. He'll find a big weight drop alarming and should agree to repeat the extensive blood work we just did a couple months ago which might give some guidance as to whether things are going ok or if I need to back off.

The only bad thing that has happened so far is last night before bed I was reading about issues with too little sodium. I have been drinking a lot more water than ever and I've eliminated most of the salt from my diet. My blood pressure has improved dramatically and I was thinking about telling my rheumatologist to reconsider my medication as I probably don't need it anymore. I felt a minor headache while trying to figure an appropriate amount of salt to add back to my diet and I panicked causing my blood pressure to jump to 178/111 before I managed to calm myself down by gulping a little salt water. While checking my blood pressure I was thinking about a friend with SBMA, Terry Waite, a couple years older, who died from a stroke in April. He was the remaining founder of the Kennedy's disease association. Bruce whose blog you found has been one of the core people of the KDA, even more so now that both the founders have died. Bruce took over posting from the administrator account of their forums but hasn't updated the avatar picture which is still of Terry.

I've known of CR for a long time but had mentally filed it away as one of many fad diets such as raw food or the Atkin's diet, thinking even if it works for some people it's probably ridiculously dangerous for others and it surely couldn't be right for me. If CR goes beyond my subjective gains, and my EMGs improve it could make some waves. There are a lot of people somewhat desperate for treatment and none of the SBMA researchers have said a word to us about the potential of CR. If we knew sooner Terry and others might still be here. It looks like there are a bunch of other "untreatable" progressive diseases, many worse than mine, such as Huntington's which is the exact same expanded sequence error on a different gene, that could benefit from CR.

Dean Pomerleau · June 11, 2016

Todd,

Thanks for the details. You certainly have faced a lot of challenges. I admire your fortitude and your rational approach to managing your condition(s). I also appreciate your candor.

A few comments:

BTW, I've read many people who practice CR also reduce protein and it appears that has a bigger impact on IGF than reducing carbohydrates.

Yes, there is some evidence that it is the protein restriction in particular that slashes IGF-1 in CR folks [1].

I looked for other options but the best I could find was a supplement, nicotinamide riboside, a NAD precursor that might promote SIRT1 activation... I started taking it at the standard dose of 125 mg twice daily. After 2 weeks without any noticeable effects positive or negative, I mustered the resolve to attempt dieting...

See my response to your other recent post for the link to recent evidence about NR. At the very least you'd need to take dose much higher than that to get anything close to what the rodents were getting when SIRT1 boost from NR was observed.

One other thing - cold exposure boosts SIRT1, although if you've now got raynaud's syndrome, that may not be a good option...

All of my lesser health issues, insomnia, digestive trouble, blood pressure, blood sugar swings, chronic pains and especially my mood have been improving at a rate I would never have dreamed possible.

That is great to hear, but cutting your calories by 50%, from 2500 to 1200/day, is still much too fast, even though you've got a lot of weight to lose. If nothing else, rapid weight loss like you're experiencing results in the release of toxins like heavy metals and pesticides (relatively) safely sequestered in fat cells, causing them to enter circulation and potentially wreak havoc on your muscles, organs, etc. Not a good idea for someone with your condition. You've been living with SBMA for decades. Why the panic now? Do yourself a big favor and take it slow(er).

For my diet, I eliminated all concentrated carbs, which is mostly what I was eating previously. I went cold turkey on fruit juices, bread, potatoes, pasta, rice, chips, cereals, sweets and everything with added sugar. The only processed foods I've been eating are mustard and pickles. My wife and I have a large garden and a flock of 9 hens, and I greatly upped my intake of garden vegetables. Most days for protein I've been eating 3 eggs, a couple ounces of lean pasture raised beef and a quarter cup of cottage cheese. Without the carbs I was eating about 1000 calories per day for a week but read that was too extreme and likely to quickly result in problems so I upped it to roughly 1200 with the addition of a few bites of fruit and an ounce of mixed tree nuts. I haven't made any attempt at true accuracy since my caloric target is rather arbitrary, I don't weigh anything and just use rough figures for calories looked up on the internet, such as 75 calories per egg. I eat two roughly equal meals a day without snacking.

That sounds like a really good start. But I really think you should add more fruits, nuts, avocado, maybe some healthy high-quality EVOO to avoid too rapid weight loss. You want to target at most 1lb of weight loss per week. Maybe in your (special) case 1.5lbs / week. In any case you need run your diet through nutrition tracking software to make sure you are meeting your basic nutritional needs. We recommend CRON-O-Meter. This is critical. You'll be shooting yourself in the foot otherwise.

But I don't know what level of restriction will optimize the rewards with respect to the risks. And I don't know if I should switch to a more long term sustainable level now.

Nobody does. And especially nobody does for someone in your unique situation. But it seems to me that if anything you need to take it slower than a healthy person, because of the extra risks for you associated with excessive muscle loss, etc. Your BP incident should be a wake up call. Bump up the calories to the point where you are only losing 1 to 1.5 lbs per week, and run your diet through CRON-O-Meter. You'll gain the benefits of CR you're already beginning to see without so many of the risks.

P.S. I'm glad you informed your doctors about your intention to try CR. But listen to their advice (and mine) and don't overdo it.

--Dean

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

[1] Aging Cell. 2008 Oct;7(5):681-7.

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3

concentration in humans.

Fontana L(1), Weiss EP, Villareal DT, Klein S, Holloszy JO.

Author information:

(1)Division of Geriatrics & Nutritional Sciences, Washington University School of

Medicine, St Louis, MO 63110, USA. lfontana@dom.wustl.edu

Comment in

Aging Cell. 2009 Apr;8(2):214; author reply 215.

Reduced function mutations in the insulin/IGF-I signaling pathway increase

maximal lifespan and health span in many species. Calorie restriction (CR)

decreases serum IGF-1 concentration by ~40%, protects against cancer and slows

aging in rodents. However, the long-term effects of CR with adequate nutrition on

circulating IGF-1 levels in humans are unknown. Here we report data from two

long-term CR studies (1 and 6 years) showing that severe CR without malnutrition

did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast,

total and free IGF-1 concentrations were significantly lower in moderately

protein-restricted individuals. Reducing protein intake from an average of 1.67 g

kg(-1) of body weight per day to 0.95 g kg(-1) of body weight per day for 3 weeks

in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194

ng mL(-1) to 152 ng mL(-1). These findings demonstrate that, unlike in rodents,

long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3

ratio in humans. In addition, our data provide evidence that protein intake is a

key determinant of circulating IGF-1 levels in humans, and suggest that reduced

protein intake may become an important component of anticancer and anti-aging

dietary interventions.

PMCID: PMC2673798

PMID: 18843793

Todd Allen · June 11, 2016

Thanks Dean! You are undoubtedly right. I had read about toxic chemicals being released from fat storage but I didn't want to think about it much and decided without any basis in knowledge that drinking more water ought to deal with little problems like that.

I've been asked how I had the will power to cut back on calories so strongly when before I reacted so poorly to hunger?

The answer is my will power is weak but my fear power is strong. I used to fear being hungry and once I got through the first few days of dieting I managed to flip it around and fear not being hungry. Then instead of being a challenge to eat so little it's been a challenge to eat so much. When I decided to increase to 1200 calories/day I went with tree nuts in part because they are supposed to be healthy but it was also appealing that they are dense and I wouldn't need to eat much more.

Now I need to be afraid of not eating the right amount and not missing micronutrients. My rational mind easily follows that, but it will take time and effort to wrap my fear around it.

As for the NR dosing I could see it was higher in the mouse model but I didn't bother to do the math to know by how much. And the translation of dosages often doesn't scale linearly with weight across species, especially those of very different sizes. And the effects of dosages also don't scale linearly so it wouldn't surprise me if it was significantly effective at the lesser dose for people, nor would it surprise me if it had no effect at all. It would be nice to have peer reviewed data for it. And the Amazon comments for it ranged wildly from it does nothing to it's the greatest. My gut tells me the odds that it's been beneficial for me are slim. By the time I finished the first bottle I was doing so much better, probably from the diet, and I was afraid to stop and got more on the chance it was part of the results I was getting. Fear doesn't scale linearly with the odds either...

Todd Allen · June 11, 2016

I've spent a lot of effort obtaining professional medical care and still it's been a hit and miss affair. It would have been great if someone had suggested dieting/CR but no one did. I have a GP primary care physician that I rarely see anymore. I go to him for flu shots, when I have a cold or I've had an accident and might need X-rays or stitches. I haven't even talked to him about dieting for SBMA yet and when I do it will be to inform him not to seek guidance. Most of my health issues have been related in one way or another to nerve dysfunction and my neurologist has increasingly directed most of my care finding other specialists to handle the details. Of those, only my rheumatologist has proven excellent actually taking into consideration my full set of health issues and taking time to research them, thoroughly explaining and asking my approval for decisions and makes sure I know and understand all test results and after each visit mails a detailed report of what he adds to my medical records to me and my neurologist. Regarding dieting for SBMA, my neurologist said he's not a nutritionist but offered to find me one. I declined though thinking that I'll do better with a referral or nutrition advice from my rheumatologist who I'll see next month. Unfortunately, his schedule is always full and short of an emergency it's hard to reschedule a visit any sooner.

So for the moment I'll make my own decisions. Dean, taking your much appreciated comments into consideration and doing my own reading I'm going to adjust for 1900 calories emphasizing protein and restricting carbs. This should net me a bit over a pound a week of loss for a while and is a lot closer to where I'll likely end up for maintenance.

200 eggs
200 dairy
200 meat/fish
200 seeds/grains
400 nuts
400 vegetables
200 fruit
100 fats/oils

I don't plan to use this rigidly but just as a guide. For instance if I have an avocado I might bill it partially to fruit and partially to fat/oils.

My will power is poor and I'm not good at making eating decisions while eating. My method for dieting has been in the morning I pick out my foods for the day, do the prep work and box up meals for lunch and dinner so that when it's time to eat I don't have to think about it. Preventing hunger and other feelings from hijacking my decisions.

I'm not going to target and compute a daily protein, fat, carb ratio. I think this gets me into a reasonable ballpark of where I want to be given my goals. If it doesn't seem to meet my goals or the goals change perhaps with input from my doctors, I'll make adjustments.

I'd prefer to skip tracking vitamins and nutrients. That would add more work and I'd rather base my daily decisions based on what I have on hand, what needs harvesting, what's ripe, what will keep and what won't, as opposed to solving systems of multiple equations looking for the substitutions to hit the numbers and then running to the store to get more chia seeds or whatever. With the start of my aggressive phase of dieting I began taking a multivitamin, expecting I was going to be short on a few things. With the jump in food I don't think I need it nearly as much. I imagine by tracking everything well there could be no need at all, but if it isn't a horrible thing to do I'm inclined to take a multivitamin once or twice a week, skip tracking/micromanaging, tell my rheumatologist what I've been doing and see how my blood tests look next month.

Dean Pomerleau · June 11, 2016

Todd,

Good job. 1900 kcal/day makes a lot more sense for you than does 1200 kcal/day. That should be sustainable, and if adequately planned, it should be nutritionally complete.

I can certainly understand your reluctance to obsess over macronutrient ratios, vitamins and minerals. You seem like such a nice & rational guy. Here is a gift from me to you - a baseline diet based on the calorie breakdown you provided, populated with CR-friendly foods and run through CRON-O-Meter to see where you'd stand nutrition-wise if you ate what I'm suggesting.

Here are the foods and quantities I picked out in order to (more or less) match what you say you'd like to eat each day:

And here is the nutrition breakdown if you ate what I'm suggesting:

Ignore the red and orange bars. The macronutrient breakdown of this diet is 34% carbs, 23% protein, and 43% fat.

Overall - eat this every day and you'll be just fine. More than fine in fact. Of course this is a pretty strict diet in terms of only containing healthy foods (well, except for the eggs/meat/dairy...). Substitutions of these food items with other, less healthy ones will (obviously) make the diet less nutritionally adequate, but small substitutions (e.g. 200kcal of cottage cheese instead of milk) will not make much difference. While personally I'd bump up the fruit & veggies, add some legumes and cut back / eliminate the eggs, meat and dairy, I can understand your wanting to do a more paleo / low-carb / ketogenic sort of diet, to keep your IGF-1 from going too low, on account of your condition. With all the volume & fiber from the fruits & veggies, along with all the protein and fat, this diet should keep you pretty satiated I expect - putting less pressure on your willpower.

Regarding the multivitamin. Eat this diet and you won't need it. It probably won't hurt to take one once or twice a week, but it is very unlikely to help you either. The one thing I recommend is to either get some sun for the vitamin D and/or supplement with at least 1000 IU/day of Vitamin D3. Adjust the sodium based on your blood pressure. If you don't add table salt, I'd also seriously consider supplementing with Iodine. One thing you don't want is thyroid problems from iodine insufficiency...

BTW, You can do this sort of analysis for yourself with CRON-O-Meter. It's really quite straightforward. And there is no need for you to track things daily if you are going to eat the same sort of diet (pretty) consistently day-to-day.

Hope this helps, and good luck!

--Dean

Todd Allen · June 12, 2016

Dean, you are amazing and incredibly helpful. I feel stupid having dismissed the software without looking at it. I had read a story about hard core CR people meeting for dinner and using spreadsheets and scales to tweak ingredient ratios to meet precise targets for the meal and I imagined CRON-O-Meter as a higher tech more targeted replacement for the spreadsheet. I'll give it a try, your list is close and I expect my results won't vary hugely from yours, though no milk and for the strawberries it's a rare day I'd even get 100 grams. We have tiny alpine strawberries and I doubt I've ever had 300 grams in a day. And I should check out how big a hit I'm taking when I steam or saute greens such as chard and some brassicas.

My wife and I were vegetarian for a long time primarily because we object to industrial farming practices, particularly for livestock. Unfortunately, I developed a condition that presented much like celiac disease except I am ok with gluten. It turned out it was protein from many different legumes including soy that I became so intolerant of that it would make me violently ill. Although I appear fine with gluten and haven't gone gluten free I was warned not to push my luck and I limit seitan and vital gluten sausages, etc. And it left a big hole in my diet.

So we keep chickens, name them, treat them like pets, offer them a great variety of quality foods that we grow or glean and we eat their eggs and eventually eat them too, usually around the age of 6. But that's been at most 2 per year, so we seek out a small amount of other animal products from local small producers who treat their animals well.

We also came to love local honey, maple syrup and organic grains that we grind into flour ourselves and many other things I thought were good but have come to think may not be so good for me. So my diet is as much by circumstance as desire.

Dean Pomerleau · June 12, 2016

Todd,

I'm happy to help. I too love alpine strawberries, and grow my own. I highly recommend giving CRON-O-Meter a try. Your "close to the earth" lifestyle sounds really appealing. And you definitely have the attitude (and incentive) to make CR work. I wish you'd stick around and become a regular contributor to our discussions here - I think you'd fit in well. But I understand if you have other fish to fry...

Either way, good luck and please keep us posted on your progress.

--Dean

Todd Allen · June 13, 2016

I think I'm in danger of sticking around and becoming insufferable.

Right now I'm deeply infatuated with CR. Today exceeded not just my unrealistic expectations but my wildest fantasies. I think I might have screwed up in that I bumped my food by 700 calories to slow the release of fat trapped toxins and this afternoon I went bicycling and I did a few hundred calories worth of exercise. Feeling good I struck out at too fast a pace. I've been like an old worn out battery that doesn't hold a charge. Just a little bit of exertion and I go flat, without any reserve, push any more and my muscles completely give out and take a long time to recover. But I didn't go flat, too fast was sustainable. Though it was a very cool day I got warm and started to sweat and I didn't want to stop. After going twice as far as I was hoping to go I decided there's always tomorrow, I don't need to find my limit today. And though I was quite shaky and a getting a little sore I was feeling better than I can remember in a very long time.

Last night I went to a little celebration at my local hackerspace. These are frequent events that I previously enjoyed, but I watched in silent horror as people were stuffing themselves on chips, soda and beer while smoke from burning grease drifted up from a grill full of burgers and brats. A veritable funeral pyre. I engaged in a little banter, sipped my water and left early. I almost felt guilty not saying anything but didn't want to come across as a born again zealot out to save all the sinners souls...

Dean Pomerleau · June 13, 2016

Todd,

I think I might have screwed up in that I bumped my food by 700 calories to slow the release of fat trapped toxins and this afternoon I went bicycling and I did a few hundred calories worth of exercise.

I'm not sure if I understand you, but if you consider a few hundred calories worth of exercise a bad thing then disabuse yourself of that idea immediately. Exercise is important for all CR folks, to maintain bone, muscle, cardiovascular and cognitive health. I suspect it is particularly important for someone with your condition. Just like with all things though - don't go overboard, at least to start with.

I almost felt guilty not saying anything [to my gluttonous friends] but didn't want to come across as a born again zealot out to save all the sinners souls.

Wow - I'm impressed. Virtually everyone who is just beginning their CR journal goes through the proselytizing phase, when they can't help but bore and alienate friends and family by incessantly blabbering about CR and its benefits. If/when they smarten up, they stop doing that, hopefully with at least some of their social network still intact. Good for you if you're able to refrain from this pitfall!

Thanks for sharing. As I said, you are more than welcome to stick around, engage in our conversations and ask any questions about diet or health that may pop up.

--Dean

Todd Allen · June 13, 2016

Dean, I'm thrilled that I'm exercising again. I had little tolerance for it previously. Post exercise recovery was increasingly slow and during that period I was prone to tremors, cramps and complete muscle failure. I was falling down almost every day, sometimes with significant injury, chipped bones, ligament damage, etc. But now I am not falling. Post exercise recovery is fast. I can push to near the point of collapse, rest a couple minutes and the shakiness subsides. After just a few hours I can repeat the exercise longer and harder than the time before. It's completely transformative.

But it also complicates things. I upped my calories to slow my rate of fat loss to reduce the rate of release of fat stored toxins. But with exercise my rate of fat loss may not subside. Should I up calories further to compensate for exercise? Could that jeopardize the benefits of CR? I haven't managed exercise induced sweating in years. Will sweat clear toxins such that I can maintain a faster rate of weight loss safely?

Dean Pomerleau · June 13, 2016

Todd,

Glad to hear you are feeling so much better, and are able to exercise again.

But with exercise my rate of fat loss may not subside. Should I up calories further to compensate for exercise? Could that jeopardize the benefits of CR? I haven't managed exercise induced sweating in years. Will sweat clear toxins such that I can maintain a faster rate of weight loss safely.

First of all, CR and its benefits are not about weight loss. As best we can tell (by my interpretation of the evidence, others may think differently...), it is about putting the body into a state where it thinks it's running an energy deficit, or at most barely squeaking by. The body reacts to this deficit by adjusting its metabolic processes to improve maintenance and repair, rather than focusing all those spare caloric resources on growth and reproduction.

Now this part is more controversial, but it is my considered opinion that it is net calorie deficit that counts, not absolute calorie intake. If at the end of the day you've expended more calories than you've taken in, then you've created a net calorie deficit. Or, in steady state, if you've eaten just enough calories to cover your basal metabolic rate and any physical activity you engaged in, your body will realize it can't be profligate with its limited leftover resources. So rather than engage in metabolically expensive growth and reproduction, it will remain in this heightened, conservative state of maintenance and repair.

While this view may not be the general concensus, my reading of the evidence and my personal experience suggests that calories burned as exercise (or cold exposure) don't "count against" you when it comes to CR health or longevity benefits, assuming there are any of the latter which are independent of the former (something I'm not very convinced of, BTW).

But more to the point, human CR without exercise is shooting yourself in the foot. We need exercise to keep our bodies and minds in good working order.

I'm just one datapoint, but I eat far higher than 1900 kcal/day but burn it off via lots of exercise and cold exposure, maintaining a BMI around 18.5 currently. My testosterone remains quite low and the other blood markers of being the "CR State" remain in place as well.

Unfortunately for you, one of those is IGF-1 My IGF-1 remains quite low, despite all the calories and exercise. But I eat a strictly vegan diet that is relatively low in protein, so perhaps with more animals products you can keep your IGF-1 higher than mine to help with your condition.

So my advice remain to keep exercising, but don't overdo it. If you start loosing more than 1 to 1.5 lbs per week on your current 1900kcal/day diet, up the calories further to slow the weight loss to remain in that range. Slow and steady wins the race. Get your blood tests in about a month when you visit your rheumatologist and see where you are at. I bet you'll be pleasantly surprised.

Either way I hope you'll continue to share your results (including blood tests) with us, and continue engaging in discussions with us both on this thread and elsewhere. You seem Iike you could have a lot to contribute.

--Dean

Dean Pomerleau · June 14, 2016

Todd (and others),

To backup my claim above that rapid weight loss releases toxins into the blood, I started a new thread. Turns out it's even worse than I suspected. See that thread for details, but the short of it is that even relatively modest weight loss of 1lb per week results in a 50% increase in persistent organic pollutants circulating in the blood, which were formerly sequestered (relatively harmlessly) in fat cells.

And note Todd, that this was a result of 1lb of total weight loss per week, not 1lb of fat loss per week, to say nothing of the 2+ lbs of fat loss you mentioned targeting in collaboration with your nutritionist. Based on this data, your rate of fat loss appears to me to be far too high to be healthy.

--Dean

Todd Allen · June 15, 2016

Dean, thanks for your efforts researching the fat stored toxins issue. I will follow it closely.

I didn't consult with a nutritionist. I consulted with my neurologist who said he wasn't a nutritionist. He thought losing a few pounds wouldn't hurt but not to over do it. He seemed slightly dismissive of the entire concept of CR as potentially therapeutic and I also don't think he believed I would sustain an aggressive diet for more than a week or two.

I got "The Longevity Diet" book from Amazon and it's helped fill in my understanding of CR. I tweaked my diet plan dropping the 200 meat calories and adding 200 of fruit and 100 more vegetables. I've never been one to eat meat daily and if I might eat some it will come from my eggs and fat budget. I was worried about eating too much carbohydrate and spiking my blood glucose and if I didn't get enough I wanted plenty of dietary protein to prevent metabolising muscle. I also wanted enough protein to keep IGF up, but it appears I was way over doing it.

The mindset of wanting to over do protein is a continuation of a poorly conceived idea that has caused much trouble. Which is that I could fight my wasting disease through eating. On the Kennedy's Disease forum I posted about my encouraging results so far having adopted calorie restriction and mentioning the scientific literature which provided the motivation to attempt this approach. I was expecting an a huge outpouring of joy from people who have been desperately popping any pill hypothesized to be beneficial before any trials demonstrate its efficacy (or lack of efficacy which so far has always been the case). But there has been no enthusiasm so far, not even enough for anyone to say I'll read up on it. Instead I get, "I've lost too much already and I don't want to risk getting any thinner."

Here's a photo of a recent meeting of people with Kennedy's. I'm not in it, but if I was I would have been in the front row seated in my mobility scooter. I would only walk at home, typically in the kitchen where I could hang on to the table and counters to steady myself. I'm walking, still assisted with a walker, and bicycling again after only a month of CR and yet there is no interest...

https://drive.google.com/file/d/0BycbustnntTzRDBISGtvTWFIM0k/view?usp=sharing

Dean Pomerleau · June 15, 2016

Todd,

I tweaked my diet plan dropping the 200 meat calories and adding 200 of fruit and 100 more vegetables.

That is a wise move from my perspective.

I was expecting an a huge outpouring of joy [about my success with CR - DP] from people who have been desperately popping any pill hypothesized to be beneficial before any trials demonstrate its efficacy (or lack of efficacy which so far has always been the case). But there has been no enthusiasm so far, not even enough for anyone to say I'll read up on it. Instead I get, "I've lost too much already and I don't want to risk getting any thinner."

Not a surprising reaction - we all get it much of the time from friends and family, even once they see us thriving on a healthy CR diet. But it is especially unsurprising from folks with Kennedy's Disease, since they are (rightfully) worried about too much muscle loss. You should be concerned about this too...

I personally wonder how much of the benefits you are observing come from cleaning up you diet, rather than restricting calories and the modest weight loss you've experienced so far. I think it is a possibility you should seriously consider. It would be great to get your BMI back to the normal range, but beyond that I'd be very conservative with the weight loss if I were in your situation. And of course, consult with your doctor.

--Dean

Todd Allen · June 15, 2016

Not a surprising reaction - we all get it much of the time from friends and family, even once they see us thriving on a healthy CR diet. But it is especially unsurprising from folks with Kennedy's Disease, since they are (rightfully) worried about too much muscle loss. You should be concerned about this too...

I personally wonder how much of the benefits you are observing come from cleaning up you diet, rather than restricting calories and the modest weight loss you've experienced so far. I think it is a possibility you should seriously consider. It would be great to get your BMI back to the normal range, but beyond that I'd be very conservative with the weight loss if I were in your situation. And of course, consult with your doctor.

--Dean

You could likely better explain the roles of better diet versus fewer calories than I.

Before I started CR I was primarily interested in whether it would have any therapeutic effect with respect to my disease process. Secondarily I was looking for some fast weight loss hoping that I might improve my ability to do things like rise to standing from a seated position or when on the ground.

Very quickly my focus started to change. A wide range of issues started to improve, perhaps some more influenced by not over eating carbohydrates and others more by less calories in total. And there was positive feedback, as I felt better, I slept better which helps in many ways.

I gave up on running and then had mostly given up on walking due to repeated, increasingly bad ankle sprains over the past 20 years. Post exertion discomfort and weakness became increasingly worse and slower to fade to the point where exercise of any type felt harmful instead of desirable. Over the past 10 years I had gone from embracing activity, to spending much time, money and thought on how to minimize it, installing a small elevator in our home, designing a mobility scooter to fit into it, and many other smaller adaptations. This approach felt like the Red Queen's race in Alice in Wonderland, having to run ever faster just to stay where you are. My doctors had been urging even less activity as I was falling almost daily and had quite a few injuries, although mostly minor.

After a couple weeks of CR, post exertion recovery was much better and I began exercising again. At first minimally, when sitting down or rising I would do it a second time. Then I began spending more time on my feet. My first trip outside with my walker for exercise I made it 50 feet from the door. But with every successive attempt I got a little farther, even just hours apart. Likewise my first bike ride I barely managed 200 feet in first gear. A couple weeks later and I am walking a half mile morning and evening with a 10 mile bike ride in the afternoon. The rate of gain is subsiding and yesterday was my first occurrence of not being able to walk quite as far as the previous try resulting in a fall, though just from momentary muscle exhaustion, not from twisting an ankle. After a couple minutes rest I stood up again unassisted and completed the walk. Before starting CR it was very hard to get up from the ground unassisted even when well rested. I may have reached a point of over doing it now at 6+ hours/day exercising, mostly light stretching, but the walking and cycling are both strenuous to near exhaustion and have reached sufficient duration for me to work up a good sweat.

Yesterday, I noticed I have regained some motion that I lost 10 years ago in two of the fingers of my left hand when it badly atrophied after a minor injury resulted in nerve damage which did not heal. After much flexing, today it seems a little bit better. I was told it would never get better and this small gain has me expecting more profound changes are coming.

Even if CR isn't directly ameliorating the SBMA disease process as I now believe, it appears to have a role in alleviating many 'unrelated' conditions that worsen with age such as obesity and cardiovascular health. If you look at the photo I posted of a gathering of people with SBMA, those still standing are significantly thinner than most of those on mobility devices. I suspect that being over weight and greater disability are strongly coupled and self reinforcing, along with heart disease, strokes, pneumonia, diabetes and so many other issues folks with SBMA seem to more frequently have. My experience so far leads me to believe that a high quality mild CR diet would likely be beneficial to the majority of those with SBMA, probably more so than it is of immediate benefit to the typical person without significant health issues.

I'm hopeful that over time more of those afflicted with SBMA and other progressive neuromuscular diseases will try some form of CR leading to improvements in their health and function and improvements in knowledge of the disease processes. If that happens quickly I would likely benefit from any insights gained and be able to better optimize my efforts toward recovery. If not, I'll continue on this path anyway and hopefully continue to benefit from what has been learned by so many others practicing CR for very different reasons.

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