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. 2021 Dec 23;58(1):16. doi: 10.3390/medicina58010016

Figure 9.

Figure 9

Vascular Contributions to Cognitive Impairment and Dementia (VCID), LOAD and FOCM. Our current society is aging, especially in the group referred to as the baby boom generation and age-related senescence. The aging society including the baby boomers is at a much higher risk for cerebro-cardiovascular disease and stroke especially with their comorbidities of aging such as hypertension and type 2 diabetes (T2DM). This slide focuses on T2DM, LOAD and age-related senescence that is ongoing as our population ages. This image does not portray inflammation; however, it is strongly related to an excess of RONS generated by aging, T2DM, LOAD. This figure points out the nuclear chromatin condensation of the amoeboid, aberrant and activated microglia cells (aMGC) and senescence, which highlights inflammation and its co-occurrence with oxidative stress via reactive oxygen nitrogen species (RONS). Of great concern is that non-replicative senescence can be induced by a variety of factors, including DNA damage (such as chromatin condensation), inflammation, mitochondrial dysfunction, oxidative stress (RONS) and importantly epigenetic disruption as related to impaired folate one-carbon metabolism (FOCM). The importance of impaired FOCM and each of the above listed factors may contribute to the inflammatory contribution of microglia senescence and nuclear chromatin condensation as depicted from our previous discussions in Section 2, Figure 3 and hence the reason for placing images C and F within this framework as well as illustrating the folate and methionine cycles. Since we have found numerous neurovascular unit remodeling changes in the diabetic db/db models, we suggest that VCID might also be considered microvascular VCID or MVCID. Impairment of the cytosolic, mitochondria and nuclear FOCM appear to be playing a role due to excessive reactive oxygen nitrogen species (RONS). Moreover, since there is obvious ongoing senescence in T2DM and LOAD it seems appropriate to ask the following question. Could improvement of impaired FOCM be a possible therapy for senescence and possibly contribute to a synalytic therapy effect? It seems appropriate to discuss this since the field of synalytic therapies is in an emerging stage of study. AGE/RAGE = advanced glycation end products and their receptor RAGE; aMGC = aberrant-activated microglia cell; aMt = aberrant mitochondria; Chr Cond = chromatin condensation.