ArticlePublisher preview availableLiterature Review

Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components

October 2022
Biogerontology 23(11)

October 2022
23(11)

DOI:10.1007/s10522-022-09995-6

Authors:

Rohit Sharma

Shoolini University

Bhawna Diwan

Shoolini University

Anamika Sharma

National Institute of Pharmaceutical Education and Research Hyderabad

Jacek M Witkowski

Medical University of Gdansk

Immunological aging is strongly associated with the observable deleterious effects of human aging. Our understanding of the causes, effects, and therapeutics of aging immune cells has long been considered within the sole purview of immunosenescence. However, it is being progressively realized that immunosenescence may not be the only determinant of immunological aging. The cellular senescence-centric theory of aging proposes a more fundamental and specific role of immune cells in regulating senescent cell (SC) burden in aging tissues that has augmented the notion of senescence immunotherapy. Now, in addition, several emerging studies are suggesting that cellular senescence itself may be prevalent in aging immune cells, and that senescent immune cells exhibiting characteristic markers of cellular senescence, similar to non-leucocyte cells, could be among the key drivers of various facets of physiological aging. The present review integrates the current knowledge related to immunosenescence and cellular senescence in immune cells per se, and aims at providing a cohesive overview of these two phenomena and their significance in immunity and aging. We present evidence and rationalize that understanding the extent and impact of cellular senescence in immune cells vis-à-vis immunosenescence is necessary for truly comprehending the notion of an ‘aged immune cell’. In addition, we also discuss the emerging significance of dietary factors such as phytochemicals, probiotic bacteria, fatty acids, and micronutrients as possible modulators of immunosenescence and cellular senescence. Evidence and opportunities related to nutritional bioactive components and immunological aging have been deliberated to augment potential nutrition-oriented immunotherapy during aging.

Identified markers of replicative senescence in T cells

…

Overview of interactions between tissue resident immune cells and senescent non-leucocyte cells with implications in immunological and systemic aging. (1) Chronic exposure to the SASP of nearby senescent cells can induce immunological dysfunctions in resident immune cells and (2) these changes can impair immune cells’ ability of immunosurveillance and efferocytosis that may ultimately result in inefficient removal of senescent cells and thus augmentation of senescent cell burden

…

Interrelationship between immune cells, cellular senescence, and aging. (1) In young organisms, SASP mediated activation of immune cells such as macrophages and NK cells identify and clear senescent cells efficiently. (2) However, in old organisms, due to cumulative effects of both cellular senescence and immunosenescence, immune cells lose the potency to manage senescent cell turnover that gradually decreases with age. (3) Inherent immune evasive attributes of senescent cells are also indicated that further highlight the complex interplay between immunity and senescent cells

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An overview of identified anti-cellular senescence and anti-immunosenescence effects of various dietary factors specific to immunological aging

…

Dietary factors can influence different aspects of aging by impacting both cellular senescence (both in immune and non-leucocyte cells) and immunosenescence (to a relatively larger extent). However, whether their known anti-immunosenescence or anti-cellular senescence effects can also translate into enhanced removal of tissue senescent cells in vivo and thus systemic improvements in organismal senescent cell burden remains to be elucidated

…

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Biogerontology (2022) 23:699–729

https://doi.org/10.1007/s10522-022-09995-6

REVIEW ARTICLE

Emerging cellular senescence‑centric understanding

ofimmunological aging andits potential modulation

throughdietary bioactive components

RohitSharma · BhawnaDiwan·

AnamikaSharma· JacekM.Witkowski

Received: 6 August 2022 / Accepted: 12 October 2022 / Published online: 19 October 2022

key drivers of various facets of physiological aging.

The present review integrates the current knowledge

related to immunosenescence and cellular senes-

cence in immune cells per se, and aims at providing

a cohesive overview of these two phenomena and

their signiﬁcance in immunity and aging. We pre-

sent evidence and rationalize that understanding the

extent and impact of cellular senescence in immune

cells vis-à-vis immunosenescence is necessary for

truly comprehending the notion of an ‘aged immune

cell’. In addition, we also discuss the emerging sig-

niﬁcance of dietary factors such as phytochemicals,

probiotic bacteria, fatty acids, and micronutrients as

possible modulators of immunosenescence and cel-

lular senescence. Evidence and opportunities related

to nutritional bioactive components and immunologi-

cal aging have been deliberated to augment potential

nutrition-oriented immunotherapy during aging.

Keywords Aging· Immunity· Inﬂamm-aging·

Cellular senescence· Immunosenescence· Nutrition

Introduction

The mammalian immune system has evolved not only

as a central instrument to protect against the invading

pathogens, but is also essential for tissue repair and

regeneration (Ding etal. 2019), as well as identiﬁca-

tion and removal of damaged host cells (Rock etal.

2011). The diverse cells of the immune system along

Abstract Immunological aging is strongly associ-

ated with the observable deleterious eﬀects of human

aging. Our understanding of the causes, eﬀects, and

therapeutics of aging immune cells has long been

considered within the sole purview of immunosenes-

cence. However, it is being progressively realized that

immunosenescence may not be the only determinant

of immunological aging. The cellular senescence-cen-

tric theory of aging proposes a more fundamental and

speciﬁc role of immune cells in regulating senescent

cell (SC) burden in aging tissues that has augmented

the notion of senescence immunotherapy. Now, in

addition, several emerging studies are suggesting that

cellular senescence itself may be prevalent in aging

immune cells, and that senescent immune cells exhib-

iting characteristic markers of cellular senescence,

similar to non-leucocyte cells, could be among the

R.Sharma(*)· B.Diwan

Faculty ofApplied Sciences andBiotechnology, Shoolini

University ofBiotechnology andManagement Sciences,

Solan173229, India

e-mail: rohit25sharma@gmail.com

A.Sharma

Department ofBiological Sciences, National

Institute ofPharmaceutical Education andResearch,

Hyderabad500037, India

J.M.Witkowski(*)

Department ofPathophysiology, Medical University

ofGdańsk, Dębinki 7, 80-211Gdańsk, Poland

e-mail: jacek.witkowski@gumed.edu.pl

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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Background With increasing age, overall health declines while systemic levels of inflammatory mediators tend to increase. Although the underlying mechanisms are poorly understood, there is a wealth of data suggesting that this so-called “inflammaging” contributes to the risk of adverse outcomes in older adults. We sought to determine whether markers of systemic inflammation were associated with antibody responses to the seasonal influenza vaccine. Results Over four seasons, hemagglutination inhibition antibody titres and ex vivo bulk peripheral blood mononuclear cell (PBMC) responses to live influenza viruses assessed via interferon (IFN)-γ/interleukin (IL)-10 production, were measured pre- and 4-weeks post-vaccination in young adults (n = 79) and older adults randomized to standard- or high-dose inactivated vaccine (n = 612). Circulating tumour necrosis factor (TNF), interleukin (IL)-6 and C-reactive protein (CRP) were also measured pre-vaccination. Post-vaccination antibody titres were significantly associated with systemic inflammatory levels; specifically, IL-6 was positively associated with A/H3N2 titres in young adults (Cohen’s d = 0.36), and in older high-dose, but not standard-dose recipients, all systemic inflammatory mediators were positively associated with A/H1N1, A/H3N2 and B titres (d = 0.10–0.45). We further show that the frequency of ILT2(+)CD57(+) CD56-Dim natural killer (NK)-cells was positively associated with both plasma IL-6 and post-vaccination A/H3N2 titres in a follow-up cohort of older high-dose recipients (n = 63). Pathway analysis suggested that ILT2(+)CD57(+) Dim NK-cells mediated 40% of the association between IL-6 and A/H3N2 titres, which may be related to underlying participant frailty. Conclusions In summary, our data suggest a complex relationship amongst influenza vaccine responses, systemic inflammation and NK-cell phenotype in older adults, which depends heavily on age, vaccine dose and possibly overall health status. While our results suggest that “inflammaging” may increase vaccine immunogenicity in older adults, it is yet to be determined whether this enhancement contributes to improved protection against influenza disease.

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AGING CELL

Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP-AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN-induced kinase 1 (PINK1)/Parkin-mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin-1 treatment. Consequently, Pink1 overexpression in combination with Torin-1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR-induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.

An update on healthspan and lifespan enhancing attributes of tea amidst the emerging understanding of aging biology

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Apr 2022

A cellular senescence-centric understanding of biological aging and age-related chronic diseases is rapidly emerging. As a result, strategies aimed at mitigating the deleterious aspects of cellular senescence are increasingly becoming desirable. Tea is a globally admired and nutrient-rich beverage that not only refreshes the senses but is also implicated in several health beneficial effects including the extension of organismal healthspan and lifespan. The present review discusses the emerging anti-cellular senescence attributes of tea consumption and provides a perspective that the anti-aging aspects of tea should be studied in the purview of cellular senescence. Current understanding of the integrative effects of the immune system and gut microbiome on cellular senescence have also been discussed with the rationale of mitigatory effects of tea. Future research directions and recommendations have been provided which may ultimately help augment tea-oriented successful and healthy aging approaches.

Long-term consumption of green tea EGCG enhances murine healthspan by mitigating multiple aspects of cellular senescence in mitotic and post-mitotic tissues, gut dysbiosis, and immunosenescence

Article

May 2022
J NUTR BIOCHEM

Cellular senescence is emerging as a major hallmark of aging, and its modulation presents an effective anti-aging strategy. This study attempted to understand the progression of cellular senescence in vivo, and whether it can be mitigated by chronic consumption of green tea catechin epigallocatechin gallate (EGCG). We profiled cellular senescence in various organs of mice at four different time-points of lifespan, and then explored the influence of EGCG consumption in impacting markers of cellular senescence, inflamm-aging, immunosenescence, and gut dysbiosis. We report that visceral adipose and intestinal tissues are highly vulnerable to cellular senescence due to an increase in DNA damage response, activation of cell cycle inhibitors, and SASP regulators. With advancing age, dysregulation in nutrient signaling mediators (AMPK/AKT/SIRT3/5), and a decrease in autophagy was also observed. Inflamm-aging markers (TNF-α/IL-1β) and splenic CD4/CD8 T cell ratio increased with age, while NK cell population decreased. Metagenomic analyses revealed an age-related decrease in the diversity of microbial species and an increase in the abundance of various pathogenic bacterial species. On the other hand, long-term EGCG consumption significantly attenuated markers of DNA damage, cell cycle inhibitors, SASP regulators, AMPK/AKT signaling, and enhanced SIRT3/5 expression and autophagy. Systemic inflamm-aging indicators decreased, while early T cell activation increased in EGCG fed animals. EGCG also suppressed the abundance of pathogenic bacteria and preserved microbial diversity. Our results suggest that adipose and intestine tissues are prone to cellular senescence and that chronic consumption of EGCG can attenuate several deleterious aspects of aging which could be implicated in developing anti-aging strategies.

Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components

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Emerging Interrelationship Between the Gut Microbiome and Cellular Senescence in the Context of Agin...