Targeting immune dysfunction in aging

Borgoni, Simone; Kudryashova, Kseniya S.; Burka, Ksenia; Magalhães, João Pedro de

doi:10.1016/j.arr.2021.101410

Cited by 106 publications

(72 citation statements)

References 210 publications

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“…Many of these targets play roles in inflammation, which is in line with the view that inflammation is associated with multiple age-related diseases and is an intrinsic and major component of the aging processes [ 71 ]. As previous studies have also reported strong overlaps of inflammation-related genes between aging and age-related diseases [ 14 ], targeting the immune dysfunction in aging could be a powerful approach for improving healthspan [ 72 ]. In addition, several strong candidate targets play roles in ECM remodeling.…”

Section: Discussionmentioning

confidence: 99%

Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine

Pun

Leung

et al. 2022

Aging

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Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.

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Section: Discussionmentioning

confidence: 99%

Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine

Pun

Leung

et al. 2022

Aging

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“…With increased age, intercellular communications change and affect endocrine and neuronal communication between cells (see López‐Otín et al, 2013 ) and references therein). Particularly impacted are immune functions, with inflammatory reactions tending to increase with age, while surveillance against pathogens and malignant cells decrease (Borgoni et al 2021 ). The overall contribution, causal or correlative, of altered cell‐to‐cell communication (beyond inflammaging (Franceschi et al, 2018 ) is not clear (but see Yousefzadeh et al, 2021 for a promising transplant study).…”

Section: Introductionmentioning

confidence: 99%

Sex‐specific aging in animals: Perspective and future directions

et al. 2022

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“…During aging, there is a progressive lack of cellular homeostasis that make organs less efficient and more susceptible to stressors. An example is the age-related decline of the immune system (termed immunesenescence) that becomes less efficient in surveilling and protecting the organism from inflammatory conditions (inflammaging), thus contributing to the organism ageing [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline

et al. 2022

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As we age, our body experiences chronic, systemic inflammation contributing to the morbidity and mortality of the elderly. The senescent immune system has been described to have a causal role in driving systemic aging and therefore may represent a key therapeutic target to prevent pathological consequences associated with aging and extend a healthy lifespan. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models halted the progression of cardiovascular diseases (CVDs) and frailty by counterbalancing chronic inflammation. In the present study, we aimed to delineate the action of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer (AAV-LAV-BPIFB4) on the deleterious age-related changes of the immune system and thereby the senescence-associated events occurring in C57BL/6J mice aged 26 months. Our in vivo data showed that 26-months-old mice had a higher frequency of CD45+SA-beta Gal+ immune cells in peripheral blood than young (4-months-old) C57BL/6J mice. Notably, AAV-LAV-BPIFB4 gene transfer in aged mice reduced the pool of peripheral immunosenescent cells that were shown to be enriched in the spleen. In addition, the proper tuning of the immune secretory phenotype (IL1βlow, IL6low, IL10high) associated with a significant reduction in SA-beta Gal-positive area of aorta from AAV-LAV treated mice. At the functional level, the reduction of senescence-associated inflammation ensured sustained NAD+ levels in the plasma of AAV-LAV-BPIFB4 old mice by preventing the NADase CD38 increase in F4/80+ tissue-resident macrophages and Ly6Chigh pro-inflammatory monocytes of the spleen and bone marrow. Finally, to validate the clinical implication of our findings, we showed that Long-living-individuals (LLIs, >95 years), which delay CVDs onset, especially if LAV-carriers, were characterized by high NAD+ levels. In conclusion, the new senotherapeutic action of LAV-BPIFB4 may offer a valuable therapeutic tool to control aging and reduce the burden of its pathophysiological disorders, such as CVDs.

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Targeting immune dysfunction in aging

Cited by 106 publications

References 210 publications

Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine

Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine

Sex‐specific aging in animals: Perspective and future directions

Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline

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