When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions.

Alzheimer’s disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease-modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms—dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity—involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases.

Cancer is widely recognized as a genetic disease based on the somatic mutation theory (SMT). This theory posits that cancer is a complex genetic disease arising from inherited or random somatic mutations in proto-oncogenes or tumor suppressor genes, leading to dysregulated cell growth. Hereditary cancer syndromes (HCSs) are genetic conditions with an underlying germline mutation that increases the risk of developing specific cancers. Numerous HCSs have been documented, and it is assumed that the inherited mutations responsible for these syndromes are the primary causes of cancers when they occur, reinforcing the SMT. In contrast, the mitochondrial metabolic theory (MMT) suggests that cancer develops due to a gradual disruption of ATP production through mitochondrial oxidative phosphorylation (OXPHOS). This leads to compensatory ATP production through substrate-level phosphorylation (SLP). Our findings indicate that no inherited mutations are fully penetrant for cancer. Therefore, these inherited mutations should be considered secondary risk factors rather than primary causes of cancer. Furthermore, we found that most, if not all, HCSs impair OXPHOS, induce oxidative stress, and exhibit increased reliance on SLP. Consequently, the heightened risk of cancer associated with HCSs likely stems from mitochondrial respiratory insufficiency and oxidative distress prevalent in these syndromes, thereby supporting the MMT.

(2001). Editorial. Current Issues in Language Planning: Vol. 2, No. 2-3, pp. 135-136.