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

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.

Figure 1

Using Cox Proportional Hazard Models, statistically significant (p<.05) interactions between age and protein group were found for all-cause and cancer mortality. Based on these models, predicted remaining life expectancy was calculated for each protein group by age at baseline. Based on results, low protein appears to have a protective effect against all-cause and cancer mortality prior to age 66, at which point it becomes detrimental. No significant interactions were found for cardiovascular disease (CVD) and diabetes mortality.

Figure 2

Serum IGF-1 levels in respondents 50–65 and 66+ reporting low, moderate, or high protein intake. IGF-1 in respondents 50–65 is significantly lower among those with low protein intake when compared to high (P=0.004). At age 66+ the difference between high and low intake becomes marginally significant (P=0.101). The cohort for which IGF-1 levels were calculated includes 2253 subjects. Of those ages 50–65 (n=1,125), 89 were in the low protein category, 854 were in the moderate protein category, and 182 were in the high protein category. Of those ages 66+ (n=1,128), 80 were in the low protein category, 867 were in the moderate protein category, and 181 were in the high protein category. Data points represent the mean ± SEM. *P<0.01.

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.

Figure 4

Effect of protein intake on body weight in young and old mice. (A) Young (18-week-old) (n=10) and old (24-month-old) (n=6) C57BL/6 mice fed a high (18%) protein diet. (B) Young (18-week-old) (n=10) and old (24-month-old) (n=6) C57BL/6 mice fed a low (4%) protein diet.