Age-related cerebral small vessel disease and inflammaging

Abstract

The continued increase in global life expectancy predicts a rising prevalence of age-related cerebral small vessel diseases (CSVD), which requires a better understanding of the underlying molecular mechanisms. In recent years, the concept of “inflammaging” has attracted increasing attention. It refers to the chronic sterile low-grade inflammation in elderly organisms and is involved in the development of a variety of age-related chronic diseases. Inflammaging is a long-term result of chronic physiological stimulation of the immune system, and various cellular and molecular mechanisms (e.g., cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, gut microbiota dysbiosis) are involved. With the deepening understanding of the etiological basis of age-related CSVD, inflammaging is considered to play an important role in its occurrence and development. One of the most critical pathophysiological mechanisms of CSVD is endothelium dysfunction and subsequent blood-brain barrier (BBB) leakage, which gives a clue in the identification of the disease by detecting circulating biological markers of BBB disruption. The regional analysis showed blood markers of vascular inflammation are often associated with deep perforating arteriopathy (DPA), while blood markers of systemic inflammation appear to be associated with cerebral amyloid angiopathy (CAA). Here, we discuss recent findings in the pathophysiology of inflammaging and their effects on the development of age-related CSVD. Furthermore, we speculate the inflammaging as a potential target for future therapeutic interventions to delay or prevent the progression of the age-related CSVD.

Clusters of Physical Frailty and Cognitive Impairment and Their Associated Comorbidities in Older Primary Care Patients

“…Differences between the CI cluster and the HF cluster in expressing cognitive impairment (74.6% vs. 11.1% of the members with MCI and a decreased average MMSE score in the CI cluster but not in the HF cluster) can also be viewed in this context. In this case, the cerebral small-vessel disease is thought to be that structural correlate of the brain that makes a link between the intensification of cardiometabolic disorders and worsening of cognitive function [ 8 ].…”

“…Fat tissue redistribution, which occurs with aging and is clinically visible as the abdominal type of obesity, in particular when it is combined with overnutrition and general overweight/obesity, may substantially contribute to inflammation and metabolic disorders associated with aging and the development of cardiometabolic age-related diseases, such as metabolic syndrome, diabetes, and CVD. Cerebral small-vessel disease, recognized as a pathologic mechanism underlying non-Alzheimer`s cognitive disorders, is considered a part of inflammaging and reflective of the overwhelming influence of metabolic and inflammatory stimuli on pathologic changes in the brain vasculature [ 8 ].…”

Cerebral small vessel disease and vascular cognitive impairment: from diagnosis to management

“…Interactions between ageing [ 10 ], environmental risk factors [ 11 ▪▪ ] and genetic variants [ 12 , 13 ] are thought to contribute to the development of sporadic SVD (Fig. 1 a).…”

Neuroinflammation in Alzheimer’s Disease

“…Aging is characterized by dysregulated immune [1] and metabolic homeostasis [2,3] where there is chronic sterile low-grade inflammation or inflammaging [4] that involves cellular senescence [5,6], immunosenescence [7][8][9][10], mitochondrial dysfunction [11,12], defective autophagy [13,14] and mitophagy [15,16], dysregulation of the ubiquitin-proteasome system [17,18], activation of the DNA damage response [19,20], meta-inflammation or metaflammation from chronic overnutrition or obesity [21,22], and gut microbiota dysbiosis [5,[23][24][25]. These are reflected by changes in circulating immune markers including C-reactive protein (CRP) [26], interleukin-6 (IL-6) [27], tumor necrosis factor alpha (TNF-α) [28] and its soluble receptors (tumor necrosis factor receptor I (TNFR-I) and tumor necrosis factor receptor II (TNFR-II)) [28], vascular cell adhesion molecule I (VCAM-I) [29], d-dimer [30], and sirtuin signaling [31,32].…”