Viva La Vida: New Clues to Living Long and Healthy

For creatures ranging from yeast to worms to mice, impaired growth hormone signaling restricts size but brings big benefits—longer life, and protection from age-related disease. Now, a 22-year longitudinal study confirms that some of these advantages extend to people, too. Valter Longo of the University of Southern California, Los Angeles, and colleagues studied people in Ecuador with growth hormone receptor deficiency and found they had extremely low rates of diabetes and cancer. The scientists also worked out a mechanism for cancer protection, tying it to reduced insulin signaling that prevents development and accumulation of DNA damage within cells. These findings were published in the February 16 issue of Science Translational Medicine.

Meanwhile, a study in the February 17 Nature might nudge us yet another step closer to the Fountain of Youth. Combining genetics with biochemical approaches in the C. elegans roundworm, Andrew Dillin and coworkers at the Salk Institute for Biological Studies in La Jolla, California, determined that two major anti-aging pathways act through CREB and CREB-regulated transcriptional coactivator.

A huge literature extols the life-extending benefits of reduced growth hormone (GH) and insulin-like growth factor-1 (IGF-1) signaling (e.g., ARF related news story on Suh et al., 2008; ARF related news story on Taguchi et al., 2007). However, Longo said, “a major goal in the aging field has been, Can we eventually translate this to extend healthy lifespan in humans (see Fontana et al., 2010 and Longo and Finch et al., 2003, reviews)?”

That’s why Longo became intrigued years ago when first author Jaime Guevara-Aguirre, an endocrinologist at the Institute of Endocrinology, Metabolism and Reproduction, Quito, Ecuador, noticed that his shortest patients seemed resistant to common diseases of aging. Since 1988, Guevara-Aguirre has studied a cohort of 90 Ecuadoreans with GH receptor gene mutations causing growth hormone receptor deficiency (GHRD, aka Laron syndrome), and more than 1,600 of their unaffected relatives, as controls. Since growth hormone acts primarily by stimulating IGF-1 release, people with mutated GH receptor produce very little IGF-1. Indeed, the GHRD subjects in the present study had serum IGF-1 levels less than one-seventh that of unaffected relatives.

Strikingly, only one person in the GHRD group developed cancer (a non-lethal epithelial tumor of the ovary) during the study, and no GHRD subjects were diagnosed with diabetes. In comparison, these age-related conditions afflicted 17 percent (273 individuals) and 5 percent (80 people) of the control group (1,606 people in total), respectively. “That is about as good as we could possibly dream of,” Longo said. Despite being more obese than controls, owing to extreme differences in stature, the GHRD patients “still don’t develop diabetes. Any doctor would say that’s just not possible,” Longo said.

He and colleagues worked to figure out how the GH receptor mutations might offer such strong protection from these diseases. For diabetes, the researchers measured fasting glucose and insulin concentrations in 16 GHRD subjects and 13 relatives. The two groups showed no glucose differences. However, GHRD patients had sharply reduced insulin levels, suggesting they were more insulin-sensitive, which could explain their resistance to diabetes, the authors propose.

To get at mechanisms underlying the GHRD subjects’ unusually low cancer rates, the scientists cultured human mammary epithelial cells, incubated them with blood from GHRD or control subjects, and watched how the cells responded to a carcinogen (hydrogen peroxide). Peroxide caused fewer DNA breaks in cells incubated with GHRD serum, yet also more caspase activity and higher death rates, compared to cells treated with control blood. Addition of IGF-1 reversed the cytotoxic effects. This suggests that in people with GHRD, “having lower blood IGF-1 levels seems to provide two protections,” Longo said. “One is to prevent DNA damage in the first place,” Longo said. “Second, it ensures that if the cell does get damaged, it’s much more prone to kill itself.” A recent study of patients with congenital IGF-1 deficiency also found that reduced IGF-1 signaling protects against cancer (Shevah and Laron, 2007).

Furthermore, in the present paper, microarrays showed that exposure to GHRD serum caused cells to turn up and down many of the genes that mediate anti-aging effects in yeast and other organisms, suggesting these same factors may postpone disease and death in people, too.

Unlike model organisms with GH receptor and IGF-1 deficiencies, the GHRD patients in the Ecuadorean study did not live longer. Further complicating matters, most of these individuals died from alcohol, accidents, and other “strange causes that are not necessarily pathology-based,” Longo said. “This completely changes the survival curve,” he noted, making it hard to assess whether the resistance to diabetes and cancer would have translated to longer lifespan in people with GHRD.

In the future, the researchers would like to examine cognition and rates of neurodegenerative disease in GHR-deficient patients. Studying the present cohort will be hard, though, as Ecuadoreans have poor healthcare and short lifespans relative to people in industrialized countries. “For studies of diabetes and cancer, you can look at 40- and 50-year-olds. With Alzheimer’s disease, you can’t,” Longo said. Instead, his team plans to assess cognitive decline in older relatives with a single copy of the GH receptor mutation. Recent studies have shown that shutting down IGF-1 signaling protects AD mouse models (ARF related news story on Cohen et al., 2009), and reduces insoluble protein deposits in aging worms (ARF related news story on David et al., 2010).

As reported in last week’s Nature, Dillin fleshed out the molecular underpinnings of two anti-aging pathways in worms. One of them is triggered by activation of 5’ AMP-activated protein kinase (AMPK), an enzyme that controls cellular energy homeostasis. AMPK springs into action when ATP levels drop and/or AMP levels rise. The other pathway slows aging through inactivation of the phosphatase calcineurin. “We have a toggle switch to play with the aging process,” Dillin told ARF. “We can throw the switch on by activating AMPK, or by inactivating the phosphatase calcineurin.” The present study identified key molecular components of the “toggle switch.”

Hints came from research showing that AMPK helps mammalian cells deal with environmental and endoplasmic reticulum stress by keeping CREB-regulated transcriptional coactivators (CRTCs) in the cytosol, thereby blocking their transcriptional function. The phosphatase calcineurin does the opposite, by promoting CRTC entry into the nucleus. That led first author William Mair and colleagues to wonder whether the AMPK and calcineurin pathways that slow aging in worms might also be mediated by CREB-regulated factors.

Several experiments bore out this idea. First, Mair and colleagues overexpressed fluorescent CRTC-1 in worms and saw the protein redistribute within cells in response to AMPK-activating stimuli (i.e., heat stress or starvation). Second, blocking CRTC-1 with RNA interference (RNAi) made the worms live longer, as did AMPK overexpression and calcineurin inhibition.

The Salk researchers also showed that AMPK and calcineurin directly target CRTC-1, and that disrupting these interactions prevented the lifespan effects. Furthermore, the team determined that CRTC-1 binds to CRH-1, the sole worm ortholog of CREB, which is required for learning and memory. “Our data indicate that CRTC-1 is the direct longevity target of both AMPK and calcineurin in C. elegans, and identify a new role for CRTCs and CREB in modulating longevity,” the authors write.

More evidence implicating calcineurin in aging and age-related disease comes from a study in this month’s issue of Aging Cell. Chris Norris and colleagues at the University of Kentucky, Lexington, report that abnormal proteolysis and activation of calcineurin occurs not only in people with Alzheimer’s disease (ARF related news story on Abdul et al., 2009), but also in seniors with mild cognitive impairment (Mohmmad Abdul et al., 2011). “For some aged individuals, irreversible proteolytic activation of calcineurin may accelerate its deleterious actions on multiple pathways involved in longevity, leading to widespread neurodegeneration and the transition to AD,” Norris wrote in an e-mail to ARF (see full comment below).—Esther Landhuis

Comments

  1. Calcineurin is increasingly recognized for its important roles in brain aging and age-related neurodegenerative diseases. Several recent studies have shown that neural calcineurin signaling is augmented in mouse models of Alzheimer’s disease (AD) (e.g., 1-3) and in human subjects with AD (2,4,5) or mild cognitive impairment (5,6), contributing to synapse dysfunction (e.g., 3), neuroinflammation (e.g., 1,7), amyloidosis (e.g., 8), impaired memory (e.g., 2), and neurodegeneration in general. The new article by Mair et al. provides important confirmation of earlier studies that reported a negative impact of calcineurin activity on longevity in C. elegans. Moreover, Mair et al. provide compelling evidence that calcineurin regulates lifespan as part of a molecular pathway involving AMPK, CRTC-1, CREB, and possibly other signaling components related to ER stress. It will be critical to further characterize these molecular interactions and their functional outcomes in mammalian models of aging and AD, especially given the vast number of interspecies differences in cellular metabolism, gene regulation, and overall biological complexity. Nevertheless, Virginia Lee and John Trojanowski’s group recently showed that systemic delivery of the calcineurin inhibitor, FK-506, increases lifespan in a mouse model of tauopathy (7), indicating that calcineurin’s role in longevity may indeed be conserved between C. elegans and mammals.

    References:

    Norris CM, Kadish I, Blalock EM, Chen KC, Thibault V, Porter NM, Landfield PW, Kraner SD. Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer's models. J Neurosci. 2005 May 4;25(18):4649-58. PubMed.

    Dineley KT, Hogan D, Zhang WR, Taglialatela G. Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem. 2007 Sep;88(2):217-24. PubMed.

    Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010 Feb 17;30(7):2636-49. PubMed.

    Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, Gong CX. Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem. 2005 Nov 11;280(45):37755-62. PubMed.

    Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Murphy MP, Levine H, Kraner SD, Norris CM. Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci. 2009 Oct 14;29(41):12957-69. PubMed.

    Mohmmad Abdul H, Baig I, Levine H, Guttmann RP, Norris CM. Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture. Aging Cell. 2011 Feb;10(1):103-13. PubMed.

    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.

    Cho HJ, Son SM, Jin SM, Hong HS, Shin DH, Kim SJ, Huh K, Mook-Jung I. RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB J. 2009 Aug;23(8):2639-49. PubMed.

    View all comments by Chris Norris

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References

News Citations

  1. How Sweet It Is! Longevity Linked to Insulin-like Growth Factor Signaling
  2. Longevity Tied to Insulin Action in Brain
  3. Long Life With Tight Plaques—Repressing IGF-1 Protects AD Mice
  4. Protein Aggregation: It’s Not Just for Disease Anymore
  5. The Skinny on NFATs—Mediators of Aβ Toxicity?

Paper Citations

  1. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42. PubMed.
  2. Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007 Jul 20;317(5836):369-72. PubMed.
  3. Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science. 2010 Apr 16;328(5976):321-6. PubMed.
  4. Longo VD, Finch CE. Evolutionary medicine: from dwarf model systems to healthy centenarians?. Science. 2003 Feb 28;299(5611):1342-6. PubMed.
  5. Shevah O, Laron Z. Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm IGF Res. 2007 Feb;17(1):54-7. PubMed.
  6. Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009 Dec 11;139(6):1157-69. PubMed.
  7. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol. 2010;8(8):e1000450. PubMed.
  8. Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Murphy MP, Levine H, Kraner SD, Norris CM. Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci. 2009 Oct 14;29(41):12957-69. PubMed.
  9. Mohmmad Abdul H, Baig I, Levine H, Guttmann RP, Norris CM. Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture. Aging Cell. 2011 Feb;10(1):103-13. PubMed.

Further Reading

Papers

  1. Mohmmad Abdul H, Baig I, Levine H, Guttmann RP, Norris CM. Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture. Aging Cell. 2011 Feb;10(1):103-13. PubMed.
  2. Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007 Jul 20;317(5836):369-72. PubMed.
  3. Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009 Dec 11;139(6):1157-69. PubMed.
  4. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42. PubMed.

Primary Papers

  1. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011 Feb 16;3(70):70ra13. PubMed.
  2. Mair W, Morantte I, Rodrigues AP, Manning G, Montminy M, Shaw RJ, Dillin A. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature. 2011 Feb 17;470(7334):404-8. PubMed.

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