Inflammaging: disturbed interplay between autophagy and inflammasomes

Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

doi:10.18632/aging.100444

Cited by 382 publications

(335 citation statements)

References 122 publications

(147 reference statements)

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“…185 Increase in oxidative stress and low-grade inflammation are the hallmarks of the aging process, which have been linked to caspase-1 activity. 186 In another study, improvement in memory was observed in rats injected intracerebroventricularly with a caspase-1 inhibitor (Ac-YVAD-CMK), 187 indicating that inhibition of caspase-1 can delay aging-associated pathologies.…”

Section: Caspase Activation During Agingmentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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Section: Caspase Activation During Agingmentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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“…Inflammation. At the organismal level, the age-related reduction in autophagy correlates with a variety of archetypal senescence-related symptoms including a general increase in smoldering inflammation that is referred to as "inflammaging" (102). Autophagy might facilitate the clearance of damaged (and potentially harmful) cells by maintaining effective efferocytosis as it reduces the propensity of leukocytes to produce pro-inflammatory cytokines (103)(104)(105).…”

Section: Autophagy Induction Suffices To Promote Longevitymentioning

confidence: 99%

Essential role for autophagy in life span extension

Madeo¹,

Zimmermann²,

Maiuri³

et al. 2015

J. Clin. Invest.

367

277

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Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity

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“…The reduced capacity of autophagy with aging generates an inflammatory condition via activation of the NLRP3 inflammasome and such disturbed interplay between autophagy and inflammaosomes is linked to the pathogenesis of T2DM, obesity, and atherosclerosis 119 . Systemic impairment of autophagy by haploinsufficiency of the essential autophagy gene (Atg7 +/-) in ob/ob mice aggravated insulin resistance with increased lipid contents and inflammatory changes 120 .…”

Section: [H3] Autophagymentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Inflammaging: disturbed interplay between autophagy and inflammasomes

Cited by 382 publications

References 122 publications

Old, new and emerging functions of caspases

Old, new and emerging functions of caspases

Essential role for autophagy in life span extension

Innate immunity in diabetes and diabetic nephropathy

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