Generated Summary
This study investigated the relationship between protein intake and mortality, cancer, and diabetes risk in a large epidemiological study of US adults (NHANES III) and in mouse models. The research combined data from a nationally representative dietary survey with cellular and mouse studies to understand the links between protein levels and sources, aging, diseases, and mortality. The study examined the associations between protein intake levels (low, moderate, and high) and various health outcomes, including all-cause mortality, cancer mortality, cardiovascular disease (CVD) mortality, and diabetes mortality. Additionally, the study explored the influence of insulin-like growth factor 1 (IGF-1) on these associations and conducted experiments in mice to verify the findings and investigate the underlying mechanisms. The findings were analyzed across different age groups to discern how these associations vary with age.
Key Findings & Statistics
- High Protein Intake and Overall Mortality (Ages 50-65): Respondents aged 50-65 reporting high protein intake had a 75% increase in overall mortality.
- Cancer Death Risk (Ages 50-65): There was a 4-fold increase in cancer death risk in the high protein intake group.
- Diabetes Mortality (All Ages): A 5-fold increase in diabetes mortality was observed across all ages with high protein intake.
- High Protein and Cancer Mortality (Ages 50-65): Subjects in the high protein group had a 74% increase in relative risk of all-cause mortality and were more than four times as likely to die of cancer (HR: 4.33; 95% CI: 1.96-9.56) when compared to those in the low protein group.
- Moderate Protein and Cancer Mortality (Ages 50-65): Compared to subjects reporting a low protein diet, subjects who consumed moderate levels of protein also had a 3-fold higher cancer mortality (HR: 3.06; 95% CI: 1.49-6.25).
- Association Between Protein and Mortality (Ages 50+): High and moderate protein consumption were positively associated with diabetes-related mortality but not with all-cause, CVD, or cancer mortality.
- Diabetes Mortality and Protein Intake: Subjects in the high protein group had a 73-fold increase in risk (HR: 73.52; 95% CI: 4.47–1,209.70) of diabetes mortality, while those in the moderate protein category had an almost 23-fold increase in the risk of diabetes mortality (HR: 22.93; 95% CI: 1.31–400.70).
- Mice Studies: Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors.
- Cancer Mortality Reduction (Older Adults): In respondents over 65, high protein intake was associated with reduced cancer and overall mortality.
- Effect of Protein on Tumor Progression (Mice): The mean tumor size was 78% larger in the high protein group compared to the low protein group (day 36, p = 0.0001; day 39, p < 0.0001).
- IGF-1 Levels and Protein Intake (Mice): Serum IGF-1 was 35% lower (p = 0.0004) in the low protein group compared to animals fed the high protein diet.
- IGFBP-1 Levels and Protein Intake (Mice): Serum IGFBP-1 was 136% higher (p = 0.003) in the low protein group compared to the high protein group.
- Tumor Incidence and Protein Intake (Mice): The tumor incidence was 100% for the high protein level (18%) group but 80% for the low protein level (4%) group in the mice models.
- Tumor Size and Protein Intake (Mice): A 45% smaller mean tumor size was also observed in the low protein group compared to the high protein group at the end of the experiment at day 53 (p = 0.0038).
- IGF-1 Levels and Protein Intake (Mice): In the low protein intake group, IGF-1 levels were reduced by 30% compared to those in the high level group (p < 0.0001).
Other Important Findings
- Low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.
- High protein intake was associated with reduced cancer and overall mortality in respondents over 65.
- The associations between total protein and all-cause or cancer mortality were eliminated or significantly reduced when controlling for the percent calories from animal protein, suggesting animal proteins are responsible for a significant portion of these relationships.
- High levels of animal proteins promote mortality, but plant-based proteins do not have the same effect.
- In mice, a low protein diet reduced circulating IGF-1 levels and increased the IGF-1 inhibitor IGFBP-1.
- In the mice models, tumor progression was strongly inhibited in the GHRKO mice when compared to progression in the control group.
- The study suggests that lower protein intake may play a role in decreasing cancer incidence and/or progression, in part, by decreasing IGF-1 and increasing the IGF-1 inhibitor IGFBP-1.
Limitations Noted in the Document
- The study is limited by the use of a single 24-hour dietary recall, which may misclassify dietary practices.
- The study acknowledges that the lack of longitudinal data on dietary consumption is a potential limitation.
- The classification of respondents into protein intake groups, as well as the sample sizes, may have affected the statistical power.
- The hazard ratios and confidence intervals may be larger than what would have been seen with a larger sample size.
- The study acknowledges the potential for misclassification of dietary practices due to the reliance on a single 24-hour dietary recall.
- The study’s analyses involving diabetes mortality among participants without diabetes at baseline or the IGF-1 subsample may have smaller sample sizes.
Conclusion
The study underscores that protein intake is linked to mortality and cancer risk in a complex and age-dependent manner. A key finding is the critical difference in the effects of high protein intake between middle-aged (50-65) and older (66+) adults. For those aged 50-65, high protein intake was significantly associated with increased overall mortality and cancer risk, while in older adults, this association reversed. The source of protein also played a significant role, with animal protein appearing to drive the adverse effects observed in middle-aged adults. The research further highlights the importance of IGF-1, with its levels being positively associated with protein consumption. The findings from the mouse models provide mechanistic insights, demonstrating how low protein diets can reduce tumor progression, potentially by modulating the IGF-1 signaling pathway. The study suggests that moderate to high levels of animal protein intake may increase mortality risks for those aged 50-65, with the risks possibly mitigated if the protein source is primarily plant-based. The research underscores that the benefits of a low protein diet observed in middle age may not extend to the elderly. The study indicates a need for personalized dietary strategies, with an emphasis on plant-based proteins, to optimize healthspan and longevity across different age groups. In line with previous studies, this research suggests that a diet in which plant-based nutrients represent the majority of the food intake is likely to maximize health benefits in all age groups, and that it may be important to avoid low protein intake and gradually adopt a moderate to high protein, preferably mostly plant-based consumption to allow the maintenance of a healthy weight and protection from frailty.
IFFS Team Summary
- 6381 subjects aged 50 and over (mean age 65) followed an average of 18 years
- 40% overall Mortality, 18% cancer mortality, 10% Cancer Mortality, 1% diabetes mortality (many followed till end of life)
- high protein intake resulted in 75% greater mortality, 4 x cancer risk than low protein diets
- this risk be was attenuated or nullified if protein was from plant sources
- in people over 65 high protein was protective
- high protein diet increased levels of diabetes in all age groups
- (also in section on Diabetes II)