What to Look for Beyond “Pathogenic” Factors in Senile Dementia? A Functional Deficiency of Ca2+ Signaling

Abstract

We have contended that senile conditions--illnesses after age 60 and fully age-penetrating, such as tooth, hearing or memory loss--are not distinct "diseases" in medical nature, because they are caused by aging. Since the pace of aging varies among individuals and is much influenced by risk factors, senile conditions will only affect some but not all elderly. However, perhaps due to its unusually heavy burdens and tremendous social pressures, senile dementia (SD) has been singled out from other senile conditions and redefined as a curable "disease" (Alzheimer's). This highly popular definition has thus opened a Pandora's box that has been confusing us up until now and warrants further scrutiny. In this article we discuss: a) what should we logically look for in SD beyond "pathogenic" factors?; b) why Ca2+, a central regulator in neurotransmission, should be the primary player in SD; c) why the functionality of Ca2+ signaling, or its vibrant wave frequency and amplitude, must undergo down-regulation during aging, though this is intriguingly accompanied by an increase of Ca2+ "levels"; d) why intervention for SD should target Ca2+ function by promoting energy metabolisms and by Ca2+ agonists such as caffeine and nicotine, but not by "antagonists" as widely believed; and e) why our study should focus on aging, not "cell death", a seemingly attractive paradigm but perhaps too late for intervention. We also seek answers for why unproven hypotheses can become dogmas and inhibit self-correcting mechanisms of science.

Elevated [Ca2+]i Levels Occur with Decreased Calpain Activity in Aged Fibroblasts and Their Reversal by Energy-Rich Compounds: New Paradigm for Alzheimer's Disease Prevention

“…In this context, our findings may reinforce the model by suggesting that the inefficient Ca 2+ signaling is a key mediator through which energy deficits can mechanistically impair neurotransmission/cognition, a highly Ca 2+dependent process [24]. Of particular interest is that the inactivated calpain may reasonably explain the agerelated accumulation of its physiological substrates, such as tau and perhaps also APP as truncated protein remnants in the brain [30,63].…”

“…However, a broad consensus today is that AD intervention should start in the pre-symptomatic, or normal aging, stage [42,43]. Thus, activating Ca 2+ signaling during aging would be a more reasonable strategy for preventing the disease [24]. But controversies remain, as it has been reported that inhibiting calpain can improve cognition in the animal models of AD [44,45] or that [Ca 2+ ] i is not altered in the fibroblasts from aged individuals in the absence of AD [36].…”

“…This paradox remains unexplained at present and awaits further studies. It should be pointed out, however, that this non-physiological phenomenon, perhaps being part of the self-destructive autolysis in cell death, should not overly complicate our studies because only the age-related, physiological changes are the basis for understanding of and designing intervention strategy for AD [24].…”

“…These studies have revealed an apparent disparity between the measured [Ca 2+ ] i levels and physiological function of Ca 2+ in aged cells. Furthermore, we have reasoned that because Ca 2+ signaling is a highly energy-dependent process [1,2] and calpain plays a critical role in life and cognition [20][21][22], it seems more likely that their physiological function should undergo down-regulation in the aging brain where energy metabolisms and cognitive ability are declining [23,24]. These and other considerations [25][26][27] have thus raised critical questions about the scientific soundness of the current hypothesis.…”

Systems Biology of Aging: Opportunities for Parkinson’s Disease

“…Mitochondrial dysfunction in response to stress in mammalian cells including mtDNA lesions has been found to elevate cytosolic Ca 2+ and to activate calcineurin, partly due to the inability of stressed mitochondria to participate in Ca 2+ uptake [11], which can activate the inhibitory protein IkBb [12]. Calcium levels have been previously reported to decline in aged fibroblasts in vitro [80], but in aging neurons the reduced dynamic of Ca 2+ fluxes, perturbing functional processes, is likely more important than Ca 2+ levels [18,41] (see Chaps. 4 and 5 for further details on Ca 2+ dynamics and the role of Calcium generally).…”