Various mechanisms have been proposed, and a molecular perspective is much awaited to account for the observed phenomena regarding aging and death. Valine and glycine are overrepresented in numerous causative factors of heart disease and Alzheimer’s disease, as well as in proteins of SARS-CoV-2 strains causing the current pandemic. Both amino acids have long carbonyl bond lengths and thus possess affinities to divalent cations, promoting the formation of insoluble salts. The insoluble and stiff calcium oxalate is stressful to cells and triggers cell senescence. Consequently valine plus glycine content can serve as a ticking aging clock as longevity genes generally encode proteins rich in valine plus glycine. Given the common characteristics of the longevity gene products, aging process may be intervened by diet, exercise and lifestyle.

Drug development for Alzheimer’s disease faces immense challenge with hundreds of failed clinical trials, and the amyloid β-protein- or Aβ-centric hypothesis is under heated debate. Cells react to environmental cues and stresses to better adapt to external milieu. However, how various organisms respond to intrinsic stresses is not fully explored. Here we propose that cells initiate a defensive response toward intrinsic stress which can be positive, negative or mixed on the host. Experiments on cellular responses to endogenous stresses could yield insight into this hypothesis. The interrogation on hydrogen bonding, secondary chemical bonding to divalent cations and their antagonism can advance biochemical understandings in this regard. Pertinent study will further our knowledge on the etiology of human disorders.

The loss of calcium-binding and the enhancement of hydrogen bonding and anion binding properties frequently occur in cancer driver mutations clusters.

The association between duodenal ulcer and ambient temperatures or seasonal transitions suggests that energy metabolism is implicated in the disorder. Since antibiotic treatment is not universally effective for duodenal ulcer recovery, the theory of Helicobacter pylori colonization cannot account for all the cases. Here we hypothesize that the shunt of Krebs cycle and other pathways of energy metabolism generate oxalate, while the insoluble and rigid calcium oxalate may cause duodenal ulcer.

Despite intense efforts, the etiology of psychiatric disorders is not fully elucidated. Sequence features of examined causative factors for schizophrenia, bipolar disorder and depression are evident, including relatively high basic amino acid content, valine plus glycine content, and content of amino acids with hydrogen bonding capacities. These hallmarks, often more pronounced in segments of the causative proteins, give rise to stressful peptides prompting the buildup of chloride ion, the generation of acids, or/and the formation of insoluble and stiff calcium salts such as calcium oxalate or/and calcium phosphate. The sequence features of these risk factors allow the generation of potent hydrogen bonding and secondary chemical bonding to divalent cations, which can be intervened by non-proton monovalent cations as in the case of lithium carbonate. Weak anion carbonate can counteract strong anion chloride. The van der Waals radius of lithium is larger and smaller than that of proton and calcium respectively, endowing its competitiveness with protons and divalent cations. The weak acid valproate has been used in the treatment of bipolar disorder and schizophrenia, and it shares partial similarity in structure to glycine with a two-carbon backbone. The aforementioned biochemical insight will further our understanding on the pathogenesis of psychiatric disorders and open up new avenues in the search of clinically useful drugs.