Faculté de médecine Pierre et Marie Curie – Site Saint-Antoine – 11ème étage
27, rue Chaligny – 75571 PARIS cedex 12
Our lab works on the molecular and cellular mechanisms of aging. We are also much interested in how the fundamental process of aging impacts on age-related disease, in particular on the etiology and progression of high prevalence Alzheimer neurodegeneration.
Somatotropic signaling and life-long tissue homeostasis
Our studies focus on the roles that insulin-like growth factors and their cognate receptor IGF-1R play in mammalian longevity. We demonstrated that IGF signaling not only exerts stringent control over postnatal growth, but also efficiently regulates cellular and organismal aging in mammals. We specifically showed that inhibiting the activation of IGF-1R prolongs lifespan and improves stress resistance (Holzenberger et al. 2003 , Xu et al. 2014). This lab also demonstrated that the functional plasticity of the somatotropic neuroendocrine axis is critical for longevity (Kappeler et al. 2008). However, the cellular mechanisms by which IGF signaling controls the aging trajectory of individuals and their tissues and organs, are still largely unknown. Recently, we showed that suppression of IGF signals in neuronal stem cells (NSC) prevents depletion of neuronal precursors and maintains youthful characteristics of neurogenesis within an aging brain (Chaker et al. 2015, 2016). These challenging results were sustained by data from extensive mathematical modeling, predicting that diminished stimulation of growth is indeed optimal for tissue aging. Thus, inhibiting growth and longevity gene IGF-1R in adult NSCs induced a gain-of-function phenotype during aging, marked by optimized management of cell renewal, lean phenotype and enhanced olfactory sensory function. These findings are first evidence that IGF signaling coordinates long-term cell replacement in vivo, and they suggest that IGF pathways impact simultaneously two major longevity mechanisms, cell resistance and cell replacement. We now expand this line of research using a new conditional model called UBIKOR (François et al. 2017).
Fig.1 - We induced IGF-1R knockout selectively in adult neuronal stem cells and found that this enhanced long-term neurogenesis in the olfactory cortex. Concomitant with the integration of many additional IGF-1R knockout neurons, olfactory function improved and male mutants progressively developed a prominent metabolic phenotype. Aged mutants were leaner and exerted tighter control over glucose metabolism. In fact, high prevalence of IGF-1R resistant neurons in the adult olfactory bulb mimics effects of food scarcity in an important sensory region of the brain. Consistently, mutants show phenotypic changes typical for systemic adaption to caloric restriction. Question marks indicate hypothetical mechanistic links between OB neurogenesis and metabolic phenotype. More details are in Chaker et al., Aging Cell 2015.
Neuronal IGF signaling and resistance to proteotoxicity
We recently demonstrated that blocking IGF signaling in adult neurons alleviates Alzheimer disease pathology through amyloid-β clearance (Gontier et al. 2015). Alzheimer disease, or AD, is a frequent and irreversible neurodegeneration, still without efficient treatment. Because experimental AD in mice responded positively to decreased insulin-like growth factor I (IGF-I) signaling (Cohen et al. 2009), we aimed to protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant to IGF signaling. To achieve that, we knocked out neuronal IGF-1R during adulthood in APP/PS1 mice, a mutant strain modeling age-dependent progression of AD pathology . Mutant mice lacking IGF-1R exhibited improved spatial memory, and their brains displayed fewer amyloid plaques, less amyloid-β (Aβ), and diminished neuroinflammation. We reported for the first time that IGF signaling has profound effects on neuronal proteostasis and maintenance of cell morphology in vivo (Gontier et al. 2015). At the same time, circulating Aβ levels were conspicuously increased. Collectively, data indicated that neuronal IGF-1R ablation, via preserved autophagic compartment and enhanced systemic elimination, offers lifelong protection from AD pathology by clearing toxic Aβ. In continuation of the above line of investigation, we lately demonstrated that functional comparison of genome-wide expression profiles between early-stage Alzheimer neurons and IGF-1R-deficient neurons reveal strongly convergent transcriptome signatures (George et al. 2017). These studies suggest that during the precocious phases of Alzheimer disease, neurons that are exposed to A proteotoxicity trigger an endogenous response that mimics the profile of neurons resistant to IGF signaling. These results underscore that neuronal IGF-1R and related signal transduction pathways are promising targets for the development of efficient Alzheimer disease treatments.
Fig.2 - Neuronal IGF-1R signaling impacts AD progression in multiple ways. Blocking IGF-1R signaling in adult neurons affects cell maintenance and protein homeostasis. Neurons change to a more compact soma and leaner dendrites (1). Autophagy defects in AD, characterized by accumulation of Aβ containing autophagic vacuoles, normalize after IGF-1R inactivation (2). IGF-1R inactivation does not change APP production or processing. Significantly less insoluble Aβ (fewer plaques) and markedly diminished soluble Aβ point to facilitated clearance of toxic peptides from the brain (3). Consequently, neuronal microenvironment is less toxic, as reflected by preserved myelin content and diminished microglial infiltration, possibly preventing less of neurons (4). Cytoarchitectural and functional changes observed after neuronal IGF-1R inactivation in the forebrain of AD improve behavioral and cognitive performances (5). Several different processes are improved in the absence of IGF signaling, suggesting that neuroprotective mechanisms are well adapted to low somatotropic tone.
Taken together, this lab identified IGF signaling pathways as key regulators of several interacting aging processes. We now focus on (1) the impact of IGF signaling on tissue homeostasis during aging, (2) the neuroprotective mechanism of neuronal IGF resistance in the context of Alzheimer neurodegeneration, and (3) the roles of systemic growth hormone and IGF signaling in coordinating health and longevity.
François JC, Aïd S, Chaker Z, Lacube P, Xu J, Fayad R, Côté F, Even P, Holzenberger M (2017) Disrupting IGF Signaling in Adult Mice Conditions Leanness, Resilient Energy Metabolism, and High Growth Hormone Pulses. Endocrinology 158: 2269-2283. https://academic.oup.com/endo/article/158/7/2269/3813249
Cintron-Colon R, Sanchez-Alavez M, Nguyen W, Mori S, Gonzalez-Rivera R, Lien T, Bartfai T, Aïd S, François JC, Holzenberger M, Conti B (2017) Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction. Proc Natl Acad Sci U S A 114: 9731-9736. https://www.pnas.org/content/114/36/9731
George C, Gontier G, Lacube P, François JC, Holzenberger M, Aïd S (2017) The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain 140: 2012-2027. https://academic.oup.com/brain/article/140/7/2012/3864005
Chaker Z, Petrovska M, Caron JB, Lacube P, Caillé I, Holzenberger M (2016) Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway. Neurobiol Aging 41: 64-72. https://www.sciencedirect.com/science/article/abs/pii/S0197458016001512?via%3Dihub
De Magalhaes Filho CD, Kappeler L, Dupont J, Solinc J, Villapol S, Denis C, Nosten-Bertrand M, Billard JM, Blaise A, Tronche F, Giros B, Charriaut-Marlangue C, Aïd S, Le Bouc Y, Holzenberger M (2017) Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin. J Cerebr Blood Flow Metab 37: 396-412. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381438/
Dansokho C, Ait Ahmed D, Aïd S, Toly-Ndour C, Chaigneau T, Calle V, Cagnard N, Holzenberger M, Piaggio E, Aucouturier P, Dorothée G (2016) Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139: 1237-1251. https://academic.oup.com/brain/article/139/4/1237/2464189
Gontier G, George C, Chaker Z, Holzenberger M, Aïd S (2015) Blocking IGF signaling in adult neurons alleviates Alzheimer’s disease pathology through amyloid-β clearance. J Neurosci 35: 11500-11513. http://www.jneurosci.org/content/35/33/11500.long
Chaker Z, Aïd S, Berry H, Holzenberger M (2015) Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging. Aging Cell 14: 847-856. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568972/
Xu J, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M (2014) Longevity effect of IGF-1R+/- mutation depends on genetic background-specific receptor activation. Aging Cell 13: 19-28. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326867/
Hégarat N, Novopashina D, Fokina AA, Boutorine AS, Venyaminova AG, Praseuth D, François JC (2014) Monitoring DNA triplex formation using multicolor fluorescence and application to insulin-like growth factor I promoter downregulation. FEBS J 281: 1417-1431. http://www.onlinelibrary.wiley.com/doi/10.1111/febs.12714/full
Durfort T, Tkach M, Meschaninova MI, Rivas MA, Elizalde PV, Venyaminova AG, Schillaci R, François JC (2012) Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model. PLoS ONE 7: e29213. http://www.journals.plos.org/plosone/article?id=10.1371/journal.pone.0029213
Xu J, Bekaert AJ, Dupont J, Rouve S, Annesi-Maesano I, De Magalhaes Filho CD, Kappeler L, Holzenberger M (2011) Exploring endocrine GH pattern in mice using rank plot analysis and random blood samples. J Endocrinol 208: 119-129. https://joe.bioscientifica.com/view/journals/joe/208/2/119.xml
Kappeler L, De Magalhaes Filho C, Leneuve P, Xu J, Brunel N, Chatziantoniou C, Le Bouc Y, Holzenberger M (2009) Early postnatal nutrition determines somatotropic function in mice. Endocrinology 150: 314-323. https://academic.oup.com/endo/article/150/1/314/2455886
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 (2009) Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139: 1157-1169. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017511/
Kappeler L, De Magalhaes FilhoC, Dupont J, LeneuveP, Cervera P, PérinL, Loudes C, Blaise A, Klein R, Epelbaum J, Le BoucY, Holzenberger M (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6: 2144-2153. http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060254