Age-related diseases as vicious cycles

Abstract

Age-related diseases (ARDs) are the leading cause of death worldwide, and contribute to 90% of mortality in developed countries. Interestingly, the mortality rates of individual ARDs increase exponentially with age. Processes described by the exponential growth function typically involve a branching chain reaction or, more generally, a positive feedback loop. Here I propose that each ARD is mediated by one or several positive feedback loops (vicious cycles). I then identify critical vicious cycles in five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. I also propose that the progression of ARDs can be halted by selectively interrupting the vicious cycles and suggest the most promising targets. An evolutionary perspective is also offered.

Context-dependent genetic architecture of Drosophila life span

“…The human population is rapidly growing older [1,2], with a concomitant increase in agerelated diseases [2,3] and societal challenges. Much of the recent increase in human life span can be attributed to improved sanitation and medical advances; however, there is also a genetic component.…”

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

“…These differences suggest that may be cell-specific changes in autophagy during senescence. Nonetheless, it appears that in the liver, autophagy likely decreases with aging and may be involved in many age-related diseases such as NAFLD and Type 2 DM [1,3,11,12,36]. In this connection, we found that both senescent AML12 cells and livers from aged mice showed late autophagy block associated with increased intracellular fat content (Figure 5a-g).…”

“…Moreover, the mRNA expression of senescence marker genes, P53, P21 and P16 were increased in the senescent AML12 cells compared to control AML12 cells (Figure 1d). Similarly, the expression of these genes also was increased in livers from old mice (100-108 week age) compared to those from young mice (12)(13)(14)(15)(16)(17)(18)(19)(20) week age) (Figure 1e). Furthermore, multiple H2O2 treatments increased senescence since there was increased activated -Gal (SA -Gal)-positive cells (Figure 2a,b) and H2A.X-positive cells containing condensed chromatin in larger nuclei (Figure 2c,d).…”

“…Such a tool would not only enable better understanding of the molecular and metabolic defects associated with aging, but also could potentially help identify druggable targets to treat age-associated chronic hepatic diseases such as fatty liver, steatohepatitis, Type 2 diabetes, hepatic fibrosis in a time-and cost-efficient manner [3, 5-7, 16, 23]. Cellular senescence and the number of senescent cells significantly increases in most tissues during aging [9,12,24]. Previous in vitro senescence models have utilized primary fibroblasts or hepatic carcinoma cells that were subjected to oxidative stress conditions or irradiation [17][18][19][20][21][22][23].…”

“…It is characterized by permanent cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype [5]. Under pathological stress conditions, excessive accumulation of senescence cells in affected tissues adversely affects the tissue's regenerative ability and creates a proinflammatory environment that can resemble various age-related disorders such as Alzheimer's disease, cancer, arthritis, cataracts, osteoporosis, atherosclerosis, hypertension, cardiovascular disease, Type 2 diabetes, and chronic liver disorders [3,5,7,[9][10][11][12]. Targeting senescent cells has the potential to delay age-associated disorders and/or reverse pathological metabolic phenotypes [3,[13][14][15][16].…”