Phase three of the CR research project on Long-Term Effects of CR on Humans has begun! This post is a “snapshot” of the research that we are involved with at the renowned Washington University School of Medicine in St. Louis. Begun in 2002, it is the first longitudinal study of CR in humans, so we are evaluated every few years and compared to “our former selves.” It is also the first study of long-term CR in humans – very different from eating fewer calories for a few weeks.

Meredith and Paul arrived at Wash U’s IRU (Intensive Research Unit) on September 29 to settle in for some of the most intensive testing we have ever experienced. The moment we arrived, the testing began. We were asked to wear transmitters to provide information on various physiological changes associated with long life in CR animals.

The really big deal came the next day, when muscle biopsies were taken on each of us. The “Day of the Biopsies” was cathartic for us. For the past eight years, we have worked to help CR-in-humans progress from mere speculation to a lifestyle designed living designed to produce cellular expression patterns that emulate those in long-lived animal studies. Finally, the moment of truth was upon us!

Or was it? Could we blow it all by letting our adrenalin run wild, a normal human response to medical testing – ruining the genetic expression patterns

that prove CR works? Or for that matter, could we have taken interfering supplements or made other dietary mistakes that also ruin CR’s genetic effects? Well, the latter is highly improbable because we have clinically tested everything in our diet. But to keep our adrenalin down, we came with a plan. *The CR Way* readers know that we use relaxation meditation to settle our bodies whenever we need to go to sleep or become calm under adversity. We coupled relaxation meditation with soft bamboo flute music from Sudir (one of our meditation teachers). It worked: Monitors of heart rate, blood pressure, and glucose levels (all of these spike when adrenalin flows) showed that these markers stayed at the same low levels throughout the procedure.

After the procedure, for any discomfort we were offered Tylenol, which we declined. Only three hours after the biopsy, we went for a mile-long walk.

And three days after, we were back following our regular routine such as walking with 30-lb weight vests.

At Wash U, we were the first of a cohort of at least 24 who will have their genes looked at. Without giving away the details, which is reserved for Drs. Fontana and Holloszy and their colleagues, we can say that our clinical results were phenomenal – as they have been in the other two phases.  Even we were surprised at just how good some outcomes were – especially certain things that concern virtually everyone, like bone health.

So, break out the unsweetened cranberry juice! Prepare to celebrate: We believe that the results of this study will positively change the lives of a lot of people. What could be better than that?  

Paul & Meredith

Following on the recent blog post about high amounts of protein intake, some may wonder about the real significance of excessive dietary stimulation of IGF-I when calorie restriction is being practiced.  Dr. Steve Spindler of UC, Riverside, said it simply at the Calorie restriction and Glucose Control Workshop, “When we feed our CR mice IGF-I, they lose their CR benefits.”

Look at what happens with CR’d animals:

Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice.

Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC.

Cancer Research. 1997 Nov 1;57(21):4667-72.         PMID: 9354418*

Debbie Josefson, San Francisco, digested this paper nicely in the “News” column of the British Medical Journal (1997;315:1327-1332 (22 November)) and on the BMJ Web site, http:// www . bmj . com / cgi / content / full / 315 / 7119 / 1327/ l, accessed Nov. 12, 2007

… restricting calorie intake by 20% reduced circulating insulin-like growth factor 1 (IGF-1) by 24% and that this reduction retarded the development and progression of an induced cancer. They monitored the effect of restricting calories and IGF-1 on the rate of development and progression of bladder cancers in p53 deficient mice (p53 is a tumour suppressor gene deficient in a variety of human tumors). A bladder carcinogen, p-cresidene, was administered to the mice to induce urothelial atypia and preneoplastic changes.

After biopsy confirmed that preneoplasia had been induced, the mice were divided into three groups. The first group (control) was fed normally; in the second group calorie intake was restricted by 20%; and the third group also had their intake restricted by 20% but had the levels of IGF-1 restored to the levels in the control group ( just like what happens when we eat extra protein). The scientists found that the mice with a restricted calorie intake had reduced rates of bladder cancer compared with the control group. Moreover when IGF-1 was restored the development of neoplasia returned to the levels in the control group, suggesting that IGF-1 may prove amenable to pharmacological intervention.

(see this for more: http://jnci.oxfordjournals.org/cgi/content/full/91/7/579)

Don’t think that because the mice in this study are p-53–deficient that the results do not apply to you. In fact, if you are a serious practitioner of The CR Way and thus probably successful in lowering glucose (see Chapter 4,” Glucose Control:  The Sweet Spot in Longevity”), you may be activating SIRT1 (see the work of Pere Puigserver for background, PMID: 15744310*) and in turn your p53 may be deactivated (see Kim EJ et al, PMID: 17964266* – click the related links for lots more on this), as well as other cellular mutation guards. This is a good thing if you practice CR with moderate protein intake. But if you surprise your evolutionarily conserved sirtuin chemistry with a bolus of protein, you may be especially vulnerable to IGF-I–stimulated mutations, ultimately turning the life-extending SIRT1 gene into a monstrous oncogene. For discussion of SIRT1 as an oncogene see this review article:

“Sirtuins in mammals: insights into their biological function.” Michan S, Sinclair D.

The Biochemical Journal. 2007 May 15;404(1):1-13. Review. PMID 17447894. *

Regarding the protein / IGF-I / cancer relationship take a look at this:

“Dietary correlates of plasma insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations.” Holmes MD, Pollak MN, Willett WC, Hankinson SE.

Cancer epidemiology, biomarkers & prevention. 2002 Sep;11(9):852-61  PMID: 12223429*

Plasma levels of insulin-like growth factor I (IGF-I) have been associated with risk of several cancers…

…We conclude that higher energy, protein, and milk intakes were associated with higher levels of IGF-I. These associations raise the possibility that diet could affect cancer risk through influencing IGF-I levels.

Testing IGF-I

Our best advice is to never trust any dietary recommendations. Rather set up your own method of objective testing. For example, try eating some nonfat yogurt (a source of easily absorbable protein) for a week and watch your IGF-I jump. Apologize to your prostate or to your breasts in advance. When you do test your

IGF-I status, you’ll want to consider at least three countervailing issues:

1. Deterioration of the pituitary – No question that if this has happened, your IGF-I may not be very responsive to dietary protein. Higher amounts of protein may be advisable in this case. If you choose to increase protein levels, keeping a close watch on cancer markers would be a good idea.

2. Growth hormone release during sleep – The primary time period for release of growth hormone in men, occurs during sleep (Davidson JR et al: “Growth hormone and cortisol secretion in relation to sleep and wakefulness.” Journal of Psychiatry and Neuroscience. 1991 Jul;16(2):96-102. PMID: 1911740*). If you eat close to bedtime, insulin – a growth hormone antagonist – blocks growth hormone release. Not a desirable way to go in my opinion.

3. The amount of hunger in your CR diet – The hunger hormone ghrelin is a principal stimulator of growth hormone and IGF-I. See:

“Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep.” Kluge M, Schüssler P, Zuber V, Kleyer S, Yassouridis A, et al. Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):1079-85. Epub 2007 Oct 22.      PMID: 17945435*

_________

 * PMID is the numerical identifier in the National Library of Medicine’s publicly accessible database: PubMed.gov. If you search PubMed using a PMID, you will retrieve the database record for the article or research paper referred to.

# # #

Is Low IGF-I a risk factor?

Limiting calories lowers growth-related activities in the body, and for good reason. The body senses that an abundance of substrate for cell division is not available so it shifts to defensive mode –becoming more resilient and efficient.

An  important aspect  of the metabolic shift that occurs with CR  is the downregulation of the Growth hormone/Insulin like growth factor 1 axis a major regulator of growth.* In discussions about CR,  some people inevitably become concerned that low IGF-I may be  a risk factor for example:

Yamaguchi H, Komamura K, Choraku M, Hirono A, Takamori N, Tamura K, Akaike M, Azuma H.  “Impact of serum insulin-like growth factor-1 on early prognosis in acute myocardial infarction.” Internal Medicine. 2008;47(9):819-25. Epub 2008 May 1.

 Drawing parallels between studies of unhealthy subjects with low IGF-I and low levels of IGF-I provoked by calorie restriction, I believe are fallacious. Studies where low levels of IGF-I are thought to contribute to early death are usually done on very ill subjects. In contrast, calorie-restricted animals are healthy. They may show lower IGF-I levels early in their CR lives, but as they get older their IGF-I levels often become higher than ad lib controls. While the ad libbers simply experience deterioration, CR’d animals frequently retain their ability to produce IGF-I and related growth hormones.

Masoro discusses this in his excellent handbook on calorie restriction and how it modulates aging: “CR also markedly decreases plasma IGF-I in young BN rats,¹ but with increasing age there is a fall in the plasma IGF-I levels in the ad libitum-fed rats and not in rats on the CR regimen.” ² So I would expect that a lifelong study of calorie restricted humans would show that when they get older, their IGF-I levels would be higher than their ad lib counterparts.

I would also expect that cells of CR’d humans would utilize the IGF-I and related hormones much more affectively than ad libbers for Masoro also reports that in aging rats, CR increases type 1 IGF-I receptors in liver, heart and skeletal muscle by 1.2 - 2.5 fold. ³

Note that in the following study, protein restriction works in a similar fashion to CR – provoking the body to adjust by increasing growth hormone/IGF-I receptors and increasing circulating growth hormone

Naranjo WM, Yakar S, Sanchez-Gomez M, Perez AU, Setser J, LERoith D. “Protein calorie restriction affects nonhepatic IGF-I production and the lymphoid system: studies using the liver-specific IGF-I gene-deleted mouse model.” Endocrinology. 2002 Jun;143(6):2233-41.

…

A low protein intake decreased the nonhepatic IGF-I secretion into the circulation, whereas it caused an increase in the level of circulating GH. This supports the view that nonhepatic IGF-I production contributes to circulating IGF-I levels. The lack of dietary protein led to an up-regulation of GH and IGF-I receptors expression in the spleen, whereas the IGF-I mRNA remained unchanged, as was demonstrated by flow cytometry and ribonuclease protection assay. B lymphocytes seem to be responsible for the up-regulated GH/IGF-I receptor expression. Northern blot analysis showed an up-regulation of IGF-binding protein-3 mRNA levels, which suggests that the protein deprivation may lead to an increased sequestration of circulating or locally synthesized IGF-I. These results support the hypothesis that the splenic GH/IGF-I axis responds to the nutritional stress caused by a low protein intake, to maintain the tissue homeostasis.

PMID: 12021187

What’s the best way then to preserve endocrine function: over-stimulation by excessive calorie or protein intake, or by some other means?

I suggest none of the above. The evidence shows that the under-stimulation of endocrine glands by calorie restriction or protein restriction preserves their function and causes cells to increase their receptivity to hormones. 

All,