Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer's disease, diabetes mellitus, and non-alcoholic steatohepatitis

Abstract

Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the "unbuilding" blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.

Fig. 1

Structural similarity between (A) Streptozotocin and (B) N-nitrosodiethylamine. Boxed regions delineate regions of homology. These compounds are alkylating agents and potent mutagens that cause cancer in various organs, induce DNA adducts leading to increased apoptosis, promote single-strand DNA breaks, and enhance production of superoxide anion, H₂O₂, and OH⁻ radicals

Fig. 2

Comparison of trends in death rates from (A) all causes, (B) Alzheimer's disease (AD), (C) Parkinson's disease (PD), (D) diabetes mellitus, (E) cerebrovascular disease, (F) chronic liver disease, (G) Human immunodeficiency virus-AIDS (HIV), (H) lymphomas, and (I) leukemias (all types) with respect to age from 1968–2005. Graphs were generated by calculating the area under curve (AUC) corresponding age-adjusted mortality rates over time. Results demonstrate that the majority of deaths from these diseases occur in the older age groups. Exceptions include chronic liver disease and HIV-AIDS.

Fig. 3

Comparison of trends in death rates from (A) all causes, (B) Alzheimer's disease (AD), (C) Parkinson's disease (PD), (D) diabetes mellitus, (E) cerebrovascular disease, (F) chronic liver disease, (G) Human immunodeficiency virus-AIDS, (H) lymphomas, and (I) leukemias (all types) over time. Note time-dependent declines in death rates within each age group for (A) all causes, (E) cerebrovascular disease and (F) chronic liver disease, and relatively stable trends with respect to (H) lymphomas and (I) leukemias, and sharp increases followed by a rapid fall in death rate due to widespread treatment with anti-retroviral agents. Only (B) AD, (C) PD, and (D) diabetes mellitus exhibit prominent increases in death rate for most age groups over time.

Fig. 4

Detailed comparison of trends in death rates for (A-E) cerebrovascular disease, (F-J) HIV, (K-O) diabetes mellitus, (P-T) Alzheimer's disease, and (U-Y) Parkinson's disease. Note the similar shapes of curves for nearly all age groups within each disease category, indicating that overall trends were not due to aging of the population.

Fig. 5

Exposure trends in the US from 1960 or 1970 to 2005. (A) US population increased nearly two-fold between 1955 and 2005. (B) Fertilizer consumption more than doubled over nearly the same interval. (C) Sales from one popular fast food franchise and (D) one major meat processing company increased more than 8-fold from 1970 to 2005. (E) In contrast, watermelon consumption remained relatively flat, and (F) cantaloupe consumption nearly doubled in parallel with population growth, but sales were minor compared with fertilizer, fast foods, and processed meats.