Organismal Aging Research Articles

Abstract LB040: P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype

Abstract Advanced age is one of the most significant risk factors for malignancy. One mechanism proposed for age-associated cancer risk is the accumulation of senescent cells in ageing tissue. These cells secrete a cocktail of pro-tumorigenic factors known as the senescence associated secretory phenotype (SASP). The SASP is driven by the NF-κB transcription factor. However, the initial triggers of NF-κB in senescence remain unclear. Here we describe a novel mechanism that triggers NF-κB and the SASP. Using multiple in vitro and in vivo models, we demonstrate accumulation and cytoplasmic to nuclear translocation of the PolI complex component, TIF-IA, upon senescence induction. siRNA knockdown revealed TIF-IA is not required for the cell cycle effects of senescence but is essential for transcription of SASP factors, nucleolar enlargement (a characteristic of senescence and marker of organismal ageing) and full senescence. We make the novel observation that in steady state, TIF-IA is targeted for autophagosomal degradation by the cargo receptor, p62, which is inhibited in senescence and promoted by inactivation of the DNA repair protein, ATM. Based on these data, we propose a model whereby the P62-TIF-IA interaction is lost downstream of DNA damage and ATM activation, which causes TIF-IA accumulation, the SASP and senescence. Using tissue from the well characterized nfkb1− / − mouse model of aging, and old and young mice, we show that TIF-IA accumulates in colonic mucosa with age, which is further enhance by nfkb1 deletion. These exciting new data identify a new role for TIF-IA and have considerable relevance to age-related cancer. Citation Format: Hazel Thoms, Lesley Stark. P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB040.

Pluripotent, germ cell competent adult stem cells underlie cnidarian regenerative ability and clonal growth

In most animals, pluripotency is irreversibly lost post gastrulation. By this stage, all embryonic cells have already committed either to one of the somatic lineages (ectoderm, endoderm, or mesoderm) or to the germline. The lack of pluripotent cells in adult life may be linked to organismal aging. Cnidarians (corals and jellyfish) are an early branch of animals that do not succumb to age, but the developmental potential of their adult stem cells remains unclear. Here, we show that adult stem cells in the cnidarian Hydractinia symbiolongicarpus (known as i-cells) are pluripotent. We transplanted single i-cells from transgenic fluorescent donors to wild-type recipients and followed them invivo in the translucent animals. Single engrafted i-cells self-renewed and contributed to all somatic lineages and gamete production, co-existing with and eventually displacing the allogeneic recipient's cells. Hence, a fully functional, sexually competent individual can derivefrom a single adult i-cell. Pluripotent i-cells enable regenerative, plant-like clonal growth in these animals.

TFEB‐dependent lysosome biogenesis is required for senescence

The accumulation of senescent cells is recognised as a driver of tissue and organismal ageing. One of the gold‐standard hallmarks of a senescent cell is an increase in lysosomal content, as measured by senescence‐associated β‐galactosidase (Senβ‐Gal) activity. The lysosome plays a central role in integrating mitogenic and stress cues to control cell metabolism, which is known to be dysregulated in senescence. Despite this, little is known about the cause and consequence of lysosomal biogenesis in senescence. We find here that lysosomes in senescent cells are dysfunctional; they have higher pH, increased evidence of membrane damage and reduced proteolytic capacity. The significant increase in lysosomal content is however sufficient to maintain degradative capacity of the cell to a level comparable to proliferating control cells. We demonstrate that increased nuclear TFEB/TFE3 supports lysosome biogenesis, is a hallmark of multiple forms of senescence and is required for senescent cell survival. TFEB/TFE3 are hypo‐phosphorylated and show constitutive nuclear localisation in senescence. Evidence suggests that several pathways may contribute to TFEB/TFE3 dysregulation in senescence.

Sesamin Metabolites Suppress the Induction of Cellular Senescence

Cellular senescence induces inflammation and is now considered one of the causes of organismal aging. Accumulating evidence indicates that age-related deterioration of mitochondrial function leads to an increase in reactive oxygen species (ROS) and DNA damage, which in turn causes cellular senescence. Thus, it is important to maintain mitochondrial function and suppress oxidative stress in order to inhibit the accumulation of senescent cells. Sesamin and its isomer episesamin are types of lignans found in sesame oil, and after being metabolized in the liver, their metabolites have been reported to exhibit antioxidant properties. However, their effects on cellular senescence remain unknown. In this study, the effects of sesamin, episesamin, and their metabolites SC1 and EC1-2 on replicative senescence were evaluated using human diploid lung fibroblasts, and TIG-3 cells. The results showed that sesamin and episesamin treatment had no effect on proliferative capacity compared to the untreated late passage group, whereas SC1 and EC1-2 treatment improved proliferative capacity and mitigated DNA damage of TIG-3 cells. Furthermore, other cellular senescence markers, such as senescence-associated secretory phenotype (SASP), mitochondria-derived ROS, and mitochondrial function (ROS/ATP ratio) were also reduced by SC1 and EC1-2 treatment. These results suggest that SC1 and EC1-2 can maintain proper mitochondrial function and suppress the induction of cellular senescence.

Turnover and replication analysis by isotope labeling (TRAIL) reveals the influence of tissue context on protein and organelle lifetimes

The lifespans of proteins range from minutes to years within mammalian tissues. Protein lifespan is relevant to organismal aging, as long‐lived proteins accrue damage over time. It is unclear how protein lifetime is shaped by tissue context, where both cell turnover and proteolytic degradation contribute to protein turnover. We develop turnover and replication analysis by 15N isotope labeling (TRAIL) to quantify protein and cell lifetimes with high precision and demonstrate that cell turnover, sequence‐encoded features, and environmental factors modulate protein lifespan across tissues. Cell and protein turnover flux are comparable in proliferative tissues, while protein turnover outpaces cell turnover in slowly proliferative tissues. Physicochemical features such as hydrophobicity, charge, and disorder influence protein turnover in slowly proliferative tissues, but protein turnover is much less sequence‐selective in highly proliferative tissues. Protein lifetimes vary nonrandomly across tissues after correcting for cell turnover. Multiprotein complexes such as the ribosome have consistent lifetimes across tissues, while mitochondria, peroxisomes, and lipid droplets have variable lifetimes. TRAIL can be used to explore how environment, aging, and disease affect tissue homeostasis.

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.

Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by "senolytics" or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.

Angiotensin II-activated mTOR pathway passes through mitochondrion in adrenocortical cells: A role of acyl CoA synthetase.

For many decades, mitochondrion has been traditionally considered as the powerhouse of the cell. In addition to energy production, this intracellular organelle plays an important role in regulating programmed cell death (apoptosis), calcium homeostasis, thermogenesis, and stress response. All of these pleiotropic functions are mostly mediated by signaling pathways that pass through the mitochondrial membranes and matrix. Not surprisingly, members of the nuclear receptor family of transcription factors have been detected in mitochondrion following hormone-induced activation (1). A similar phenomenon seems to occur with members of the mammalian/mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), indicating that subcellular compartmentalization of signaling proteins matters a lot (2). mTORC1 and mTORC2 are 2 distinct protein complexes that both consist of an intracellular serine-threonine kinase, named mTOR, which is activated by the PI3K-Akt pathway. mTORC1 is activated by several growth factors, including the epidermal growth factor (EGF) and the insulin-like growth factor 1/2, and plays a fundamental role in protein and lipid biosynthesis, ribosome biogenesis, as well as in the aging of organisms (2). On the other hand, mTORC2 is also activated by growth factors and participates in cell survival, cytoskeletal organization, metabolism, and cell migration (2). The protein members of both mTORC complexes have been detected in many subcellular compartments, including cytoplasm and nucleus, as well as in lysosomes, peroxisomes, and the Golgi apparatus. However, the mitochondrial localization of these proteins had not been clearly documented until recently (2). Independently of subcellular compartmentalization, Su et al demonstrated that the mTOR signaling cascade was overexpressed in the zona glomerulosa of patients with aldosterone-producing adenomas, indicating that mTOR inhibitors might be used to treat hyperaldosteronism (3). Soon after, De Martino and collaborators investigated the expression of the mTOR pathway in normal adrenal tissues, adrenal hyperplasia, adrenocortical adenomas, and adrenocortical carcinomas (4). They also studied the effects of sirolimus, a well-known mTOR inhibitor, on survival and cortisol secretion in a number of primary cultures of human adrenocortical tumors. Interestingly, the authors found that the mTOR pathway was activated in a subset of adrenocortical tumors and that certain cases of adrenocortical carcinomas were sirolimus-responsive (4), indicating that mTOR inhibitors might be further used to suppress adrenal steroid production. Furthermore, although angiotensin II (Ang II) had been shown to activate the mTOR pathway in esophageal carcinoma (2), a similar Ang II-induced activation of the mTOR signaling cascade had not been reported in adrenal cortex.

HCINAP alleviates senescence by regulating MDM2 via p14ARF and the HDAC1/CoREST complex.

Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network. Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid the discovery of new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPase protein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditis elegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulated senescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence. Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On one hand, hCINAP decreases p53 stability by attenuating the interaction between p14ARF and MDM2; on the other hand, hCINAP promotes MDM2 transcription via inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering HDAC1/CoREST complex integrity. Collectively, our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlying the aging process.

Enhanced Levels of Peroxisome-Derived H2O2 Do Not Induce Pexophagy but Impair Autophagic Flux in HEK-293 and HeLa Cells

Peroxisomes are functionally specialized organelles that harbor multiple hydrogen peroxide (H2O2)-producing and -degrading enzymes. Given that this oxidant functions as a major redox signaling agent, peroxisomes have the intrinsic ability to mediate and modulate H2O2-driven processes, including autophagy. However, it remains unclear whether changes in peroxisomal H2O2 (po-H2O2) emission impact the autophagic process and to which extent peroxisomes with a disturbed H2O2 metabolism are selectively eliminated through a process called "pexophagy". To address these issues, we generated and validated HEK-293 and HeLa pexophagy reporter cell lines in which the production of po-H2O2 can be modulated. We demonstrate that (i) po-H2O2 can oxidatively modify multiple selective autophagy receptors and core autophagy proteins, (ii) neither modest nor robust levels of po-H2O2 emission act as a prime determinant of pexophagy, and (iii) high levels of po-H2O2 impair autophagic flux by oxidative inhibition of enzymes involved in LC3II formation. Unexpectedly, our analyses also revealed that the autophagy receptor optineurin can be recruited to peroxisomes, thereby triggering pexophagy. In summary, these findings lend support to the idea that, during cellular and organismal aging, peroxisomes with enhanced H2O2 release can escape pexophagy and downregulate autophagic activity, thereby perpetuating the accumulation of damaged and toxic cellular debris.

A Cellular Senescence-Centric Integrated Approach to Understanding Organismal Aging.

Aging remains the fundamental cause of the increased rate of morbidity and mortality in the elderly. Despite continuing research, an integrative and holistic understanding of the molecular mechanisms and effects of aging is still elusive. This presents a major challenge in biogerontology, and therefore novel strategies aimed at integrating the multifaceted nature of aging for the identification and development of successful therapeutic targets are highly desirable. At present, cellular senescence, immunosenescence, and gut microbiota dysbiosis are key known modulators of aging. However, a cellular senescence-centric integrative view that relates to the seemingly distinct processes of immunosenescence and gut microbiota dysbiosis can be envisaged, which implies a more inclusive and targetable understanding of aging. The present manuscript discusses the emerging evidence and significance of cellular senescence vis-à-vis immunosenescence and gut microbiota dysbiosis in the development of potential anti-aging therapies. Underlying interconnections and mechanisms amongst these individual modulators have been deliberated to present a more coherent and tangible understanding of biological aging. It is emphasized that aging be studied within the integrative purview of these processes that may ultimately help devise a new inclusive and consolidated theory of aging with well-defined therapeutic targets.

The emerging roles of tRNAs and tRNA-derived fragments during aging: Lessons from studies on model organisms.

Aging is a gradual decline of various functions of organisms resulting in diminished abilities to protect against the environmental damage and reinforce the physiological harmony. Age-related functional declines have been thought to be passive and not regulated. However, studies on numerous model organisms, from yeast to mammals, exposed that the mechanisms of lifespan regulation are remarkably conserved throughout the evolution. Following the pioneering genetic studies in C. elegans, it has been shown that the genes related to the longevity are conserved in yeast, flies and mice. For a long time, tRNAs have been only considered as molecules transporting amino acids to the ribosome during translation. Nonetheless, it has become apparent from many biological studies that tRNAs are entangled in a variety of physiological and pathological processes. This review focuses on the emerging roles of tRNA-associated processes in aging and lifespan of model organisms. More specificaly, we present a summary on the importance of tRNA metabolism, epitranscriptome and possible roles of tRNA-derived fragments in aging and lifespan regulation. Better understanding of the basic mechanisms of aging could lead to the development of new diagnostics and treatments for aging-related diseases.

Coupling of autophagy and the mitochondrial intrinsic apoptosis pathway modulates proteostasis and ageing in Caenorhabditis elegans

Mitochondria preserve metabolic homeostasis and integrate stress signals, to trigger cytoprotective, or cell death pathways. Mitochondrial homeostasis and function decline with age. The mechanisms underlying the deterioration of mitochondrial homeostasis during ageing, or in age-associated pathologies, remain unclear. Here, we show that CISD-1, a mitochondrial iron-sulfur cluster binding protein, implicated in the pathogenesis of Wolfram neurodegenerative syndrome type 2, modulates longevity in the nematode Caenorhabditis elegans by engaging autophagy and the mitochondrial intrinsic apoptosis pathway. The anti-apoptotic protein CED-9 is the downstream effector that mediates CISD-1-dependent effects on proteostasis, neuronal integrity and lifespan. Moreover, intracellular iron abundance is critical for CISD-1 function, since mild iron supplementation is sufficient to decelerate ageing and partly ameliorate the disturbed mitochondrial bioenergetics and proteostasis of CISD-1 deficient animals. Our findings reveal that CISD-1 serves as a mechanistic link between autophagy and the apoptotic pathway in mitochondria to differentially modulate organismal proteostasis and ageing, and suggest novel approaches which could facilitate the treatment of Wolfram Syndrome or related diseases.

Telomerase as a possible key to bypass reproductive cost.

Three widely accepted assumptions are based on telomere research in human cells: (i) telomere length is a determinant of replicative ageing; (ii) telomerase activity in somatic cells supports the proliferative capacity of the cells and thus contributes to their regenerative potential and is a determinant of organismal lifespan; and (iii) the lack of telomerase activity acts as a tumour suppression mechanism. However, from a broader view, the link between telomere biology and cellular and organismal ageing, as well as tumour development, remains of debate, as I demonstrate with numerous examples of invertebrate and vertebrate species. Consequently, I propose a novel hypothesis that telomere biology, via somatic telomerase activity, reflects ageing rate from the perspective of species reproduction strategy.

Potential of Microalgae as Functional Foods Applied to Mitochondria Protection and Healthy Aging Promotion

The rapid aging of the Western countries’ populations makes increasingly necessary the promotion of healthy lifestyles in order to prevent/delay the onset of age-related diseases. The use of functional foods can significantly help to achieve this aim, thanks to the contribution of biologically active compounds suitable to protect cellular and metabolic homeostasis from damage caused by stress factors. Indeed, the excessive production of reactive oxygen species (ROS), favored by incorrect eating and behavioral habits, are considered causal elements of oxidative stress, which in turn favors tissue and organism aging. Microalgae represent a convenient and suitable functional food because of their extraordinary ability to concentrate various active compounds, comprising omega-3 polyunsaturated fatty acids, sterols, phenolic compounds, carotenoids and others. Within cells, mitochondria are the cellular organelles most affected by the accumulation of molecular damage produced by oxidative stress. Since, in addition to producing the chemical energy for cellular metabolism, mitochondria control numerous cell cycle regulation processes, including intrinsic apoptosis, responses to inflammatory signals and other biochemical pathways, their dysfunction is considered decisive for many pathologies. Among these, some degenerative diseases of the nervous system, cardiovascular system, kidney function and even cancer are found. From this viewpoint, bioactive compounds of microalgae, in addition to possessing high antioxidant properties, can enhance mitochondrial functionality by modulating the expression of numerous protective factors and enzymes, which in turn regulate some essential biochemical pathways for the preservation of the functional integrity of the cell. Here, we summarize the current knowledge on the role played by microalgal compounds in the regulation of the mitochondrial life cycle, expression of protective and reparative enzymes, regulation of intrinsic apoptosis and modulation of some key biochemical pathways. Special attention was paid to the composition of some cultivable microalgae strains selected for their high content of active compounds suitable to protect and improve mitochondrial functions.

Somatic nuclear blebbing in Caenorhabditis elegans is not a feature of organismal aging but a potential indicator of germline proliferation in early adulthood.

Abnormal nuclear morphology is suggested to be a hallmark of aging and one such abnormality is nuclear blebbing. However, little is known about whether and how nuclear blebbing participates in animal aging, and what regulates it. In this study, we show that the frequency of nuclear blebbing in the hypodermis increases during aging in wild-type C. elegans. These nuclear blebs are enveloped by the nuclear lamina, the inner and the outer nuclear membrane, and 42% of them contain chromatin. Although nuclear blebbing could lead to DNA loss if chromatin-containing blebs detach and fuse with lysosomes, we find by time-lapse imaging that nuclear blebs rarely detach, and the estimated lifetime of a nuclear bleb is 772 h or 32 days. The amount of DNA lost through nuclear blebbing is estimated to be about 0.1% of the total DNA loss by adult Day 11. Furthermore, the frequency of nuclear blebbing does not correlate with the rate of aging in C. elegans. Old age does not necessarily induce nuclear blebbing, neither does starvation, heat stress, or oxidative stress. Intriguingly, we find that proliferation of germ cells promotes nuclear blebbing.

Circular RNAs: New players involved in the regulation of cognition and cognitive diseases.

Circular RNAs (circRNAs), a type of covalently closed endogenous single-stranded RNA, have been regarded as the byproducts of the aberrant splicing of genes without any biological functions. Recently, with the development of high-throughput sequencing and bioinformatics, thousands of circRNAs and their differential biological functions have been identified. Except for the great advances in identifying circRNA roles in tumor progression, diagnosis, and treatment, accumulated evidence shows that circRNAs are enriched in the brain, especially in the synapse, and dynamically change with the development or aging of organisms. Because of the specific roles of synapses in higher-order cognitive functions, circRNAs may not only participate in cognitive functions in normal physiological conditions but also lead to cognition-related diseases after abnormal regulation of their expression or location. Thus, in this review, we summarized the progress of studies looking at the role of circRNA in cognitive function, as well as their involvement in the occurrence, development, prognosis, and treatment of cognitive-related diseases, including autism, depression, and Alzheimer's diseases.

Network topologies for maximal organismal health span and lifespan.

The population dynamics of human health and mortality can be jointly captured by complex network models using scale-free network topology. To validate and understand the choice of scale-free networks, we investigate which network topologies maximize either lifespan or health span. Using the Generic Network Model (GNM) of organismal aging, we find that both health span and lifespan are maximized with a "star" motif. Furthermore, these optimized topologies exhibit maximal lifespans that are not far above the maximal observed human lifespan. To approximate the complexity requirements of the underlying physiological function, we then constrain network entropies. Using non-parametric stochastic optimization of network structure, we find that disassortative scale-free networks exhibit the best of both lifespan and health span. Parametric optimization of scale-free networks behaves similarly. We further find that higher maximum connectivity and lower minimum connectivity networks enhance both maximal lifespans and health spans by allowing for more disassortative networks. Our results validate the scale-free network assumption of the GNM and indicate the importance of disassortativity in preserving health and longevity in the face of damage propagation during aging. Our results highlight the advantages provided by disassortative scale-free networks in biological organisms and subsystems.

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond.

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import.

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death.

The deletion of the gene coding for poly(ADP-ribose) polymerase-1 (PARP1) or its pharmacological inhibition protects mice against cerebral ischemia and Parkinson's disease. In sharp contrast, PARP1 inhibitors are in clinical use for the eradication of vulnerable cancer cells. It appears that excessive PARP1 activation is involved in a specific cell death pathway called parthanatos, while inhibition of PARP1 in cancer cells amplifies DNA damage to a lethal level. Hence, PARP1 plays a context-dependent role in cell fate decisions. In addition, it appears that PARP1 plays an ambiguous role in organismal aging.

Exosome Release Delays Senescence by Disposing of Obsolete Biomolecules.

Accumulation of obsolete biomolecules can accelerate cell senescence and organism aging. The two efficient intracellular systems, namely the ubiquitin-proteasome system and the autophagy-lysosome system, play important roles in dealing with cellular wastes. However, how multicellular organisms orchestrate the processing of obsolete molecules and delay aging remains unclear. Herein, it is shown that prevention of exosome release by GW4869 or Rab27a-/- accelerated senescence in various cells and mice, while stimulating exosome release by nutrient restriction delays aging. Interestingly, exosomes isolate from serum-deprived cells or diet-restricted human plasma, enriched with garbage biomolecules, including misfolded proteins, oxidized lipids, and proteins. These cellular wastes can be englobed by macrophages, eventually, for disintegration in vivo. Inhibition of nutrient-sensing mTORC1 signaling increases exosome release and delays senescence, while constitutive activation of mTORC1 reduces exosome secretion and exacerbates senescence in vitro and in mice. Notably, inhibition of exosome release attenuates nutrient restriction- or rapamycin-delayed senescence, supporting a key role for exosome secretion in this process. This study reveals a potential mechanism by which stimulated exosome release delays aging in multicellular organisms, by orchestrating the harmful biomolecules disposal via exosomes and macrophages.