Hallmarks of aging: An expanding universe

López-Otín C., Pietrocola F., Roiz-Valle D., Galluzzi L., Kroemer G.

Both aging and cancer are characterized by a series of partially overlapping “hallmarks” that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common “meta-hallmarks,” while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly “antagonistic hallmarks.” Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly. Both aging and cancer are characterized by a series of partially overlapping “hallmarks” that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common “meta-hallmarks,” while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly “antagonistic hallmarks.” Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.

Xu L., Zhang Q., Dou X., Wang Y., Wang J., Zhou Y., Liu X., Li J.

Advanced maternal age is characterized by declines in the quantity and quality of oocytes in the ovaries, and the aging process is accompanied by changes in gut microbiota composition. However, little is known about the relationship between gut microbiota and ovarian aging. By using fecal microbiota transplantation (FMT) to transplant material from young (5-week-old) into aged (42-week-old) mice, we find that the composition of gut microbiota in FMT-treated mice presents a "younger-like phenotype" and an increase of commensal bacteria, such as Bifidobacterium and Ruminococcaceae. Moreover, the FMT-treated mice show increased anti-inflammatory cytokine IL-4 and decreased pro-inflammatory cytokine IFN-γ. Fertility tests for assessing ovarian function reveal that the first litter size of female FMT-treated mice is significantly higher than that of the non-FMT group. Morphology analysis demonstrates a dramatic decrease in follicle atresia and apoptosis as well as an increase in cellular proliferation in the ovaries of the FMT-treated mice. Our results also show that FMT improves the immune microenvironment in aged ovaries, with decreased macrophages and macrophage-derived multinucleated giant cells (MNGCs). These results suggest that FMT from young donors could be a good choice for delaying ovarian aging.

Simon M., Yang J., Gigas J., Earley E.J., Hillpot E., Zhang L., Zagorulya M., Tombline G., Gilbert M., Yuen S.L., Pope A., Van Meter M., Emmrich S., Firsanov D., Athreya A., et. al.

Alder J.K., Armanios M.

Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange.

Ponting C.P., Haerty W.

Do long noncoding RNAs (lncRNAs) contribute little or substantively to human biology? To address how lncRNA loci and their transcripts, structures, interactions, and functions contribute to human traits and disease, we adopt a genome-wide perspective. We intend to provoke alternative interpretation of questionable evidence and thorough inquiry into unsubstantiated claims. We discuss pitfalls of lncRNA experimental and computational methods as well as opposing interpretations of their results. The majority of evidence, we argue, indicates that most lncRNA transcript models reflect transcriptional noise or provide minor regulatory roles, leaving relatively few human lncRNAs that contribute centrally to human development, physiology, or behavior. These important few tend to be spliced and better conserved but lack a simple syntax relating sequence to structure and mechanism, and so resist simple categorization. This genome-wide view should help investigators prioritize individual lncRNAs based on their likely contribution to human biology.

Della Valle F., Reddy P., Yamamoto M., Liu P., Saera-Vila A., Bensaddek D., Zhang H., Prieto Martinez J., Abassi L., Celii M., Ocampo A., Nuñez Delicado E., Mangiavacchi A., Aiese Cigliano R., Rodriguez Esteban C., et. al.

Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that LINE-1 ( Long Interspersed Nuclear Element-1; L1 ) RNA accumulation was an early event in both typical and atypical human progeroid syndromes. L1 RNA negatively regulated the enzymatic activity of the histone-lysine N -methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of L1 RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as p16 , p21 , activating transcription factor 3 ( ATF3 ), matrix metallopeptidase 13 ( MMP13 ), interleukin 1a ( IL1a ), BTG anti-proliferation factor 2 ( BTG2 ), and growth arrest and DNA damage inducible beta ( GADD45b ). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after L1 RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of L1 RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.

Roux A.E., Zhang C., Paw J., Zavala-Solorio J., Malahias E., Vijay T., Kolumam G., Kenyon C., Kimmel J.C.

Partial pluripotent reprogramming can reverse features of aging in mammalian cells, but the impact on somatic identity and the necessity of individual reprogramming factors remain unknown. Here, we used single-cell genomics to map the identity trajectory induced by partial reprogramming in multiple murine cell types and dissected the influence of each factor by screening all Yamanaka Factor subsets with pooled single-cell screens. We found that partial reprogramming restored youthful expression in adipogenic and mesenchymal stem cells but also temporarily suppressed somatic identity programs. Our pooled screens revealed that many subsets of the Yamanaka Factors both restore youthful expression and suppress somatic identity, but these effects were not tightly entangled. We also found that a multipotent reprogramming strategy inspired by amphibian regeneration restored youthful expression in myogenic cells. Our results suggest that various sets of reprogramming factors can restore youthful expression with varying degrees of somatic identity suppression. A record of this paper's Transparent Peer Review process is included in the supplemental information.

Sladitschek-Martens H.L., Guarnieri A., Brumana G., Zanconato F., Battilana G., Xiccato R.L., Panciera T., Forcato M., Bicciato S., Guzzardo V., Fassan M., Ulliana L., Gandin A., Tripodo C., Foiani M., et. al.

Ageing is intimately connected to the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS–STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS–STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing. tDeclining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING signalling, a pillar of innate immunity, so sustaining YAP/TAZ mechanosignalling or inhibiting STING present promising approaches for limiting senescence-associated inflammation and improving healthy ageing.

Michel M., Benítez-Buelga C., Calvo P.A., Hanna B.M., Mortusewicz O., Masuyer G., Davies J., Wallner O., Sanjiv K., Albers J.J., Castañeda-Zegarra S., Jemth A., Visnes T., Sastre-Perona A., Danda A.N., et. al.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Abdellatif M., Trummer-Herbst V., Heberle A.M., Humnig A., Pendl T., Durand S., Cerrato G., Hofer S.J., Islam M., Voglhuber J., Ramos Pittol J.M., Kepp O., Hoefler G., Schmidt A., Rainer P.P., et. al.

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Acosta-Rodríguez V., Rijo-Ferreira F., Izumo M., Xu P., Wight-Carter M., Green C.B., Takahashi J.S.

Caloric restriction (CR) prolongs life span, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour feeding and 22-hour fasting, raising the question of if it is calories, fasting, or time of day that is the cause of this increased life span. We show here that 30% CR was sufficient to extend the life span by 10%; however, a daily fasting interval and circadian alignment of feeding acted together to extend life span by 35% in male C57BL/6J mice. These effects were independent of body weight. Aging induced widespread increases in gene expression associated with inflammation and decreases in the expression of genes encoding components of metabolic pathways in liver from ad libitum–fed mice. CR at night ameliorated these aging-related changes. Our results show that circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.

Ma S., Wang S., Ye Y., Ren J., Chen R., Li W., Li J., Zhao L., Zhao Q., Sun G., Jing Y., Zuo Y., Xiong M., Yang Y., Wang Q., et. al.

The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.

Cani P.D., Depommier C., Derrien M., Everard A., de Vos W.M.

Ever since Akkermansia muciniphila was discovered and characterized two decades ago, numerous studies have shown that the lack or decreased abundance of this commensal bacterium was linked with multiple diseases (such as obesity, diabetes, liver steatosis, inflammation and response to cancer immunotherapies). Although primarily based on simple associations, there are nowadays an increasing number of studies moving from correlations to causality. The causal evidence derived from a variety of animal models performed in different laboratories and recently was also recapitulated in a human proof-of-concept trial. In this Review, we cover the history of the discovery of A. muciniphila and summarize the numerous findings and main mechanisms of action by which this intestinal symbiont improves health. A comparison of this microorganism with other next-generation beneficial microorganisms that are being developed is also made. This Review covers the discovery of Akkermansia muciniphila and its association with health and disease, including metabolic diseases. Insights into underlying mechanisms for how A. muciniphila improves health are given as are comparisons with other next-generation beneficial microorganisms.

He W., Yang M., Jiang Y., He C., Sun Y., Liu L., Huang M., Jiao Y., Chen K., Hou J., Huang M., Xu Y., Feng X., Liu Y., Guo Q., et. al.

A specific bone capillary subtype, namely type H vessels, with high expression of CD31 and endomucin, was shown to couple angiogenesis and osteogenesis recently. The number of type H vessels in bone tissue declines with age, and the underlying mechanism for this reduction is unclear. Here, we report that microRNA-188-3p (miR-188-3p) involves this process. miRNA-188-3p expression is upregulated in skeletal endothelium and negatively regulates the formation of type H vessels during ageing. Mice with depletion of miR-188 showed an alleviated age-related decline in type H vessels. In contrast, endothelial-specific overexpression of miR-188-3p reduced the number of type H vessels, leading to decreased bone mass and delayed bone regeneration. Mechanistically, we found that miR-188 inhibits type H vessel formation by directly targeting integrin β3 in endothelial cells. Our findings indicate that miR-188-3p is a key regulator of type H vessel formation and may be a potential therapeutic target for preventing bone loss and accelerating bone regeneration.

Singh A., D’Amico D., Andreux P.A., Fouassier A.M., Blanco-Bose W., Evans M., Aebischer P., Auwerx J., Rinsch C.

Summary Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic compound Urolithin A (Mitopure), a known mitophagy activator, at two doses for 4 months (NCT03464500). The data show significant improvements in muscle strength (∼12%) with intake of Urolithin A. We observe clinically meaningful improvements with Urolithin A on aerobic endurance (peak oxygen oxygen consumption [VO2]) and physical performance (6 min walk test) but do not notice a significant improvement on peak power output (primary endpoint). Levels of plasma acylcarnitines and C-reactive proteins are significantly lower with Urolithin A, indicating higher mitochondrial efficiency and reduced inflammation. We also examine expression of proteins linked to mitophagy and mitochondrial metabolism in skeletal muscle and find a significant increase with Urolithin A administration. This study highlights the benefit of Urolithin A to improve muscle performance.

Zhao Y., Chen L., Jiang S., Wu Z., Xiang Q., Lin J., Tian S., Sun Z., Sun C., Li W.

García-Vílchez R., Guallar D.

Chen J., Wang W., Yu F., Wang X., He Y., Chen K.

Zhang D., Zhu Y., Shen Z., Ma S., Liu S., Lu Z.

Jalševac F., Segú H., Balaguer F., Ocaña T., Moreira R., Abad-Jordà L., Gràcia-Sancho J., Fernández-Iglesias A., Andres-Lacueva C., Martínez-Huélamo M., Beltran-Debon R., Rodríguez-Gallego E., Terra X., Ardévol A., Pinent M.

Cheng D., Lian W., Jia X., Wang T., Sun W., Jia Z., Liu Y., Ni C.

Hu C.

Zhang H., Xiong J., Wang Q., Song Q., Meng L., Zhang H., Bao Y., Liu F., Xiao Y.

Song C., Yang J., Gu Z.

Pahal S., Mainali N., Balasubramaniam M., Shmookler Reis R.J., Ayyadevara S.

Kong L., Li S., Fu Y., Cai Q., Zhai Z., Liang J., Ma T.

Skowronska-Krawczyk D., Finnemann S.C., Grant M.B., Held K., Hu Z., Lu Y.R., Malek G., Sennlaub F., Sparrow J., D’Amore P.A.

Liang Z., Tang Q., Liang H., Liang X., Fu C., Kang W., Zhang Y., Lv P.

Khalaf F., Barayan D., Saldanha S., Jeschke M.G.

Zhou W., Yu C., Meng T., Jiang Q., Yu F., Yuan H.