Lamin in inflammation and aging
Introduction
Chronic systemic inflammation without apparent infection in elderly humans is often referred to as the ‘inflammaging’ phenotype, and is primarily characterized by elevated levels of circulating pro-inflammatory cytokines [1, 2, 3, 4, 5, 6]. Epidemiological studies have found a strong correlation between the inflammaging phenotype and the presence of several aging-associated pathologies [7, 8, 9]. Genome-wide association studies have implicated several genes that function in immune, inflammatory and stress responses as being modifiers of longevity and health span [10].
Understanding the contribution of inflammation to aging has been pursued for many years with much effort aimed at identifying biomarkers of aging and cellular events that might serve as triggers for inflammatory responses. While conceptually straightforward, identifying cellular events has been very difficult, and is still largely correlative. Further, understanding the consequences of inflammation on aging presents its own challenges because, in part, many age-related diseases such as cardiovascular disease and osteoarthritis invoke strong inflammatory responses [11].
Recent studies have implicated the involvement of the nuclear intermediate filament proteins, the lamins, in aging-related inflammation. Here we will first introduce the general functions of lamins and then discuss the studies connecting these proteins to inflammation and aging.
Section snippets
Nuclear lamins
Nuclear lamins are classed as type V intermediate filaments. There are two lamin subtypes, A-type and B-type, which are distinguished by their protein sequences, physical properties and expression profiles. In humans, the A-type lamin is encoded by LMNA, while two separate genes, LMNB1 and LMNB2, encode the B-type lamins. In Drosophila, the subject of some discussion below, the A-type and B-type lamins (LAMC and LAM) are encoded by LamC and Lam, respectively.
Alternative splicing of the human
Lamin-A: aging and inflammation
Hutchinson-Gilford Progeria Syndrome (HGPS) is an exceptionally rare disorder that resembles premature aging. Most HGPS patients harbor the same LMNA mutation, a de novo C1824T change that enhances the use of a cryptic splice site and leads to the production of a permanently farnesylated form of lamin-A [31•, 32•]. This aberrant form of lamin-A, termed progerin, causes nuclear blebbing, down-regulation of some nuclear envelope proteins, accumulation of DNA damage and accelerated cellular
Lamin B: aging and inflammation
Human and mouse primary cell lines have a finite replicative lifespan (Hayflick limit) when cultured in vitro. This phenomenon, more commonly called replicative senescence, is characterized by cessation of cell division, increased secretion of inflammatory factors and changes in cell morphology and chromatin organization [45, 46]. Recent studies have found that the replicative senescence of cultured mammalian fibroblasts is accompanied by lamin-B1 reduction [47••, 48••, 49]. The induction of
Lamin-B may maintain tissue homeostasis by controlling gene expression
To gain insight into the role of lamin-B in maintaining the fat body organ, we performed RNA-seq to identify gene expression differences in fat bodies from young (5 days), old (50 days) and 5-day fat bodies that had LAM prematurely depleted by a tissue-specific RNAi [55••]. Gene ontology (GO) analyses revealed that age-associated LAM loss was characterized by changes in genes primarily belonging to immune, metabolic, proteolysis, and oxidative pathways (Figure 2a). Depletion of LAM in young fat
Conclusions and future considerations
Aging is multifactorial, and different theories that center on cellular damage have been proposed to explain this phenomenon [62]. While the relationship between the nuclear lamina and various forms of cellular damage has not been extensive explored, there are examples in the literature that suggest that protein homeostatic mechanisms, such as autophagy and the Ubiquitin Proteasome System, are particularly relevant. For instance, autophagy activation with either rapamycin or temsirolimus
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the Ellison Medical Foundation and by NIH grants GM056312 and GM106023.
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