Inflammation and Immune System Activation in Aging: A Mathematical Approach

Nikas, Jason B.

The seven genes [C4A (C4B), ADORA3, MS4A7, BCL6, CD44, C3AR1, and HLA-DRB1], which are the constituent input variables of the model (F 1 super variable), and all of which are -in terms of function -inflammation or immune system activation genes (Table 1) , were all found to be over-expressed in the old subjects compared with the young subjects (Table 1) . C4A (C4B) has been observed to be over-expressed in patients with Huntington disease 8 and Alzheimer disease 9 , in mice with rheumatoid arthritis 10 , etc. ADORA3 has been found to be over-expressed in the hippocampus of patients with Parkinson disease 11 , in patients with astrocytomas 12 , etc. MS4A7 has been observed to be over-expressed in mice with rheumatoid arthritis 10 . BCL6 has been observed to be over-expressed in patients with Huntington disease 13 , with ischemic stroke 14 , with rheumatoid arthritis 15 , with B-cell lymphoma 16 , etc. CD44 has been found to be over-expressed in patients with systemic lupus erythematosus 17 , with immune thrombocytopenia 18 , with schwannomas 19 , with Huntington disease 8 , and numerous other diseases and conditions. Over-expression of C3AR1 has been observed in patients with severe acute respiratory syndrome 20 , with asthma 21 , etc., while overexpression of HLA-DRB1 has been observed in patients with multiple sclerosis 22 , with rheumatoid arthritis 23 , with Duchenne muscular dystrophy 24 , etc. Previous studies using animal models have observed associations between aging and inflammation in connection with the hippocampus, the neocortex, and the cerebellum 25,26 . Using animal models or human subjects with early-stage neurodegenerative diseases, such as Alzheimer, other studies have observed a link between neuroinflammation and deficits in synaptic plasticity, especially long-term potentiation (LTP) in the hippocampus, which is associated with longterm memory consolidation [27] [28] [29] [30] [31] [32] 2 . The fact that definitive causality cannot be established here notwithstanding -in other words, whether it is the normal aging process that induces inflammation/ immune-system-overactivity, or whether the vice versa occurs, or whether another, hitherto unspecified, process engenders the normal aging process, which in turn induces inflammation/immune-systemoveractivity, or whether that unspecified process engenders inflammation/immune-system-overactivity, which in turn induces the normal aging process -the results of my study support a direct causal link between the normal aging process and the process of inflammation/immune-system-overactivity. When considered collectively, therefore, the results of my study and all of the above observations from the other aforementioned studies point to a plausible theory on the normal aging process. At some point in time, chronic, low-level inflammation establishes itself and elicits a corresponding chronic immune response and activity. These two conjugate processes ultimately are responsible for a gradual loss of synaptic plasticity, particularly LTP in the hippocampus, accompanied with a minimal neuronal loss 33, 34, [1] [2] [3] . It is this loss of synaptic plasticity -at least in the hippocampus part of the brain -that is associated with the phenotypical changes of normal aging.