Cell Metab. 2014 Mar 4;19(3):407-17. doi: 10.1016/j.cmet.2014.02.006.

Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population.

Levine ME¹, Suarez JA², Brandhorst S², Balasubramanian P², Cheng CW², Madia F³, Fontana L⁴, Mirisola MG⁵, Guevara-Aguirre J⁶, Wan J², Passarino G⁷, Kennedy BK⁸, Wei M², Cohen P², Crimmins EM¹, Longo VD⁹.

Author information

1: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA.
2: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA; Longevity Institute, University of Southern California, Los Angeles, CA 90033, USA.
3: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA; EURL ECVAM, Institute for Health & Consumer Protection, European Commission Joint Research Centre, Ispra (VA) 21027, Italy.
4: Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Clinical and Experimental Sciences, Brescia University School of Medicine, Brescia 25123, Italy; CEINGE Biotecnologie Avanzate, Napoli 80145, Italy.
5: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA; Longevity Institute, University of Southern California, Los Angeles, CA 90033, USA; Dipartimento di Biopatologia e Metodologie Biomediche, Universita' di Palermo, Palermo 90127, Italy.
6: Universidad San Francisco de Quito & Instituto IEMYR, Quito 17-1200-841, Ecuador.
7: Department of Biology, Ecology and Earth Science, University of Calabria, Rende 87036, Italy.
8: Buck Institute for Research on Aging, Novato, CA 94945, USA.
9: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA; Longevity Institute, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: vlongo@usc.edu.

Abstract

Mice and humans with growth hormone receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality. Respondents aged 50-65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years. These associations were either abolished or attenuated if the proteins were plant derived. Conversely, high protein intake was associated with reduced cancer and overall mortality in respondents over 65, but a 5-fold increase in diabetes mortality across all ages. Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

Comment in

Nutrition. Diet studies challenge thinking on proteins versus carbs. [Science. 2014]

PMID:: 24606898
PMCID:: PMC3988204
DOI:: 10.1016/j.cmet.2014.02.006

[Indexed for MEDLINE]

Free PMC Article

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Figure 3

(A) Tumor incidence in 18-week-old male C57BL/6 mice implanted with 20,000 melanoma (B16) cells, and fed either a high protein (18%; n=10) or low protein (4%; n=10) diet. (B) B16 Tumor volume progression in (18wk) C57BL/6 male mice fed either a high protein (n=10) or low protein (n=10) diet. (C) IGF-1 at day 16 in (18wk) male C57BL/6 mice fed either a high protein (n=5) or low protein (n=5) diet. (D) IGFBP-1 at day 16 in male (18wk) C57BL/6 mice fed either a high protein (n=10) or low protein (n=10) diet. (E) B16 melanomatumor progression in 10-month old female GHRKO mice (n=5) vs age-matched littermate controls (Ctrl; n=7). (F) Tumor incidence in 12-week-old female BALB/c mice implanted with 20,000 cell breast cancer (4T1) fed either a high protein (18%; n=10) or low protein (7%; n=10) diet. (G) 4T1 breast cancer progression in female (12wk) BALB/c mice fed either a high protein (n=10) or low protein (n=10)diet. (H) IGF-1 at day 16 in female (12wk) BALB/c mice fed either a high animal protein (n=5) or low animal protein (n=5) diet. (I) IGFBP-1 at day 16 in female (12wk) BALB/c mice fed either a high animal protein (n=10) or low animal protein (n=10) diet. (J) IGF-1 at day 16 in female (12wk) BALB/c mice fed either a high soy protein (n=5) or low soy protein (n=5) diet. (K) IGFBP-1 at day 16 in female (12wk) BALB/c mice fed either high soy protein (n=10) or low soy protein (n=10) diet. (L) Survival and (M) DNA mutation frequency of yeast exposed to a 0.5x, 1x, or 2x concentration of a standard amino acid mix. (N) PDS and STRE activity in yeast grown in media containing only Trp, Leu. and His compared to those grown in the presence of all AA. (O) Ras2 deletion protects against oxidative stress-induced genomic instability measured as DNA mutation frequency (Can^r) in wild-type (DBY746) and ras2Δ mutants chronically exposed to 1mM H₂O_2.(P) A model for the effect of amino acids on aging and genomic instability in S. cerevisiae. Amino acids activate the Tor-Sch9 and Ras-cAMP-PKA pathway also activated by glucose and promote age- and oxidative stress-dependent genomic instability in part via reduced activity of Gis1 and Msn2/4. In all graphs, data points represent the mean of the biological replicates ± SEM. *P<0.05, **P<0.01, ***P<0.001.

Low Protein Intake is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population

Cell Metab. ;19(3):407-417.