Other prolongevity interventions on gut microbiota

      The probiotic Lactobacillus plantarum GKM3 promotes longevity and alleviates age-related cognitive impairment in the SAMP8 mouse model of accelerated aging.89 Interventions on gut microbiota composition also restored the age-linked decline in microglial maturation and function which causes altered brain plasticity and promotes neurodegeneration. Recolonization experiments or administration of gut microbiota metabolites, such as SCFAs, prevented the age-associated decline of beneficial Bifidobacterium, increased Akkermansia abundance, and restored microglial function in middle-aged mice.94 Moreover, caloric restriction diets induce structural changes of the gut microbiome increasing the abundance of Lactobacillus and other species that influence healthy aging. The gut microbiotainduced inflammaging and the consequent increase in insulin resistance can also be reversed by restoring abundance of beneficial SCFA-producing bacteria, such as A. muciniphila, in agedmice and macaques.293 Similarly, a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers showed that oral administration of pasteurized A. muciniphila improved insulin sensitivity reduced insulinemia and plasma total cholesterol levels.95 Collectively, these results underscore the causal links between aging and dysbiosis and suggest that interventions aimed at restoring a youthful microbiome may extend healthspan and lifespan.

INTEGRATION OF HALLMARKS

      All the 12 hallmarks of aging are strongly related among each other. For example, genomic instability (including that caused by telomere shortening) crosstalks to epigenetic alterations (e.g., through the loss-of-function mutation of epigenetic modifiers such as TET2), loss of proteostasis (e.g., due to the production of mutated, misfolded proteins), disabled macroautophagy (e.g., through the capacity of autophagy to remove supernumerary centrosomes, extranuclear chromatin, and cytosolic DNA), deregulated nutrient-sensing (e.g., because SIRT6 is an NAD+sensor involved in DNA repair but also responding to nutrient scarcity), mitochondrial dysfunction (e.g., due to the mutation of mtDNA), cellular senescence (e.g., because DNA damage triggers senescence), altered intercellular communication (e.g., by hampering activation of communication pathways), chronic inflammation (e.g., because CHIP and leakage of DNA into the cytosol induce inflammation), and dysbiosis (e.g., because mutations in intestinal cells favors dysbiosis, whereas specific microbial proteins and metabolites act as mutagens). Similar functional relationships can be listed for most if not all hallmarks of aging, illustrating their formidable interconnectivity.

      This entanglement is also visible at the level of experimental anti-aging interventions that often simultaneously target several hallmarks. Thus, SIRT activators including NAD+ precursors attenuate genomic instability (via DNA repair), epigenetic alterations (via histone deacetylation), loss of proteostasis (via the removal of protein aggregates), disabled macroautophagy (via autophagy enhancement), deregulated nutrient-sensing (via activation of nutrient scarcity sensors), and mitochondrial dysfunction (via an increase in mitophagy-dependent quality control).176 Spermidine complexes to DNA (hence counteracting genomic instability), affects translation (avoiding loss of proteostasis), stimulates macroautophagy, reverses lymphocyte senescence, prevents the exhaustion of muscle stem cells, maintains circadian rhythms, suppresses inflammation, stimulates cancer immunosurveillance, and is produced by intestinal bacteria. 294 Metformin has a pleiotropic mode of action including induction of autophagy, activation of the nutrient scarcity sensor AMPK, inhibition of mitochondrial respiration, alleviation of adipocyte senescence, suppression of inflammation, and favorable shifts in the gut microbiota.210 Similarly, maintenance of eubiosis by oral supplementation of A. muciniphila stimulates intestinal autophagy, reduces metabolic syndrome, dampens inflammation, and enhances anticancer immune responses.295 Indeed, a notable feature of effective anti-aging interventions, such as lowered insulin/IGF-1 signaling296 and disruption of the TORC1 complex,296,297 is the diversity of mechanisms by which they target different aging hallmarks in different tissues to maintain healthspan of the whole organism.

      Although each of the 12 hallmarks of aging can be targeted one by one, yielding tangible benefits for healthspan and lifespan (Table 1), there is some kind of hierarchy among them (Figure 1). Thus, as we initially proposed,1 the primary hallmarks, which reflect damages affecting the genome, telomeres, epigenome, proteome, and organelles, progressively accumulate with time and unambiguously contribute to the aging process.298 The antagonistic hallmarks, which reflect responses to damage, play a more nuanced role in the aging process. For example, trophic signaling and anabolic reactions activated by nutrientsensing have beneficial actions in youth but are largely pro-ageing later on. Thus, in an archetypal case of antagonistic pleiotropy, the nutrient-sensing network contributes to organ development until young adulthood but plays a detrimental role beyond this stage. Additionally, reversible and low-dose mitochondrial dysfunction can stimulate beneficial counterreactions (via mitohormesis), whereas limited and spatially confined levels of cellular senescence contribute to the suppression of oncogenesis and improve wound healing. Finally, the integrative hallmarks arise when the accumulated damage inflicted by the primary and antagonistic hallmarks cannot be compensated any more, resulting in stem cell exhaustion, intercellular communication alterations including ECM damage, chronic inflammation, and dysbiosis, which together dictate the pace of aging.

      Recently, we postulated the existence of eight hallmarks of health,146 which include organizational features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to perturbation (homeostatic resilience, hormetic regulation, and repair and regeneration). Undoubtedly, aging is linked to progressive deterioration of these eight hallmarks of health, implying a ramping incapacity to maintain spatial compartmentalization (with the consequent loss of integrity of internal and external barriers, as well as the incapacity to contain perturbations of such barriers in space and time), to assure long-term homeostasis (with reduced capacity of recycling and turnover, inefficient coordination among different systems via integrated circuitries, and desynchronization of ultradian, circadian, or infradian rhythms), and to adequately respond to stress by complete repair and regeneration, homeostatic resilience, and hormetic regulation (Figure 7). This decline affects all eight strata of organismal organization, across different classes of molecules (such as DNA, RNA, proteins, and metabolites), organelles (such as nuclei, mitochondria, and lysosomes), cell types (such as parenchymatous, auxiliary/stromal, and inflammatory/immune cells), supracellular units constituting the minimal functional entities of organs, entire organs within their anatomical boundaries, organ systems (such as the gastrointestinal, respiratory, and urinary tracts), systemic circuitries (with their endocrine, neurological, lymphatic, and vascular connections), as well as the meta-organism (that includes the microbiota). As a result, the 12 hallmarks of aging are interconnected to the eight hallmarks of failing health and the eight strata of organismal organization (Figure 7), creating a multidimensional space of interactions that may explain some features of the aging process.

      Heterochronic parabiosis experiments, in which the vascular systems of young and old mice are connected, may illustrate best the importance of systemic regulatory factors (such as hormones and circulating cells) on the aging process. This phenomenon has been extensively characterized at the level of single-cell transcriptomics, yielding a spatiotemporal map of the capacity of the young system to rejuvenate an older one or, vice versa, the ability of pro-aging factors to precipitate the senescence of young cells.74,75 This type of experiment demonstrates that aging relies on the integration of cell-autonomous and non-cell-autonomous mechanisms that also have been revealed in Drosophila (in which stimulation of autophagy in the intestine is sufficient to extend lifespan of the entire organism)120 and mice (in which injection of a few thousands of senescent fibroblasts is sufficient to trigger invalidating osteoarthritis).299 Hence, pro-aging and anti-aging mechanisms can be communicated among distinct cell types, perhaps explaining that ‘‘normal’’ aging usually affects multiple organs in a closeto-synchronous fashion, at difference with ‘‘pathological’’ aging in which time-dependent diseases precociously manifest in specific locations, in the form of initially isolated cardiovascular, oncological, or neurodegenerative disorders. However, the distinction between normal and pathological aging is debatable,300 and some progeroid syndromes manifest signs of incomplete or segmental aging, as exemplified by the absence of a central nervous phenotype in HGPS.

      In view of the spectacular progress of developing longevity strategies in mammalian model organisms and initial clinical trials (Table 1), it will be important to develop rational strategies for intervening into human aging. The question arises to which extent strategies for extending human healthspan should be based on the avoidance of age-accelerating environmental factors (such as pollution, stress, inadequate physical activity, and unhealthy diets, often unavoidable in a context of poverty, precariousness, and wartime), the adoption of health-promoting lifestyle factors (such as diet, exercise, regular sleeping patterns, and social activities), the administration of relatively non-specific, pleiotropic drugs (exemplified by NAD+ precursors, metformin, spermidine, or MTORC1 inhibitors), or more specific medical interventions. Such specific treatments may involve pharmacological agents—with the prospective of a broad implementation, genetic or cell-based therapies—with rather complex logistics and elevated costs, or bioengineering methods for surgical tissue replacement, which most likely will mainly remain in the realm of experimentation. Given the multiplicity of hallmarks offering therapeutic strategies for decelerating, halting, or reversing aging, it will be interesting to evaluate combination regimens with the scope of maximizing benefits and minimizing side effects. The question remains open whether such healthspan and lifespan extending prophylactic treatments will profit from personalization based on individual patient characteristics determined by the genetic, epigenetic, metabolomic, or phenotypic assessments of aging clocks.

      Aging is not yet a recognized target for drug development or for treatment. For this reason, the first clinical trials evaluating antiaging interventions must deal with the prevention or mitigation of age-associated pathologies rather than aging itself. Although such trials have been designed to target high-risk populations (such as patients with myocardial infarction and laboratory signs of inflammation in the CANTOS trial or patients with frailty or cardiovascular events to be enrolled in future metformin-related trials) and to measure the manifestation of a second cardiovascular event or aggravation of frailty, there is a risk that they are programmed too late, which is of significant concern. Indeed, at this point, academic geroscience may raise or fall as the function of the outcome of the first randomized, double-blinded phase 3 trials. The new directions of the hallmarks of aging may provide an improved framework for the development of effective interventions aimed at the extension of healthy longevity.

ACKNOWLEDGMENTS

      We apologize for omitting relevant works and citations due to space constraints. We acknowledge all members of our laboratories for helpful comments during the elaboration of this manuscript. We thank Jose´M.P.Freije for critical reading of the manuscript. C.L-O. is supported by grants from the European Research Council (ERC Advanced Grant, DeAge), Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III, and La Caixa Foundation (HR17-00221). The Instituto Universitario de Oncologı´a is supported byFundacio´n Bancaria Caja de Ahorros de Asturias. M.B. is funded by AgenciaEstatal de Investigacio´n (AEI/MCI/10.13039/501100011033, project RETOS SAF2017-82623-R), cofunded by European Regional Development Fund, ‘‘A way of making Europe’’; Comunidad de Madrid with the Sinergy Project COVIDPREclinicalMODels-CM and the ERC under the European Union’s Horizon 2020 research and innovation programme (grant 882385) through the project ERC-AvG SHELTERINS. The CNIO, certified as Severo Ochoa Centre of Excellence by AEI/MCI/10.13039/501100011033, is supported by the Spanish Government through the Instituto de Salud Carlos III. L.P. is supported by Horizon 2020 Framework Programme 741989, the Max Planck Society, and the BBSRC. M.S. is funded by a core grant from the IRB, La Caixa Foundation, the Milky Way Research Foundation, and Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca Consolidat 2017 SGR 282). G.K. is supported by the Ligue contre le Cancer (e ´quipe labellise´ e); Agence National de la Recherche (ANR)–Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cance ´ ropo ˆ le Ile-de-France; Fondation pour la Recherche Me´ dicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases; the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer; Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18- IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Universite ´ de Paris ANR-18-IDEX-0001.

DECLARATION OF INTERESTS

      M.A.B. is founder and shareholder of Life Length, SL, which commercializes telomere length measurements for biomedical use. M.S. is shareholder and advisor of Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc.; and shareholder of Senolytic Therapeutics, Inc., and Life Biosciences, Inc. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma; consulting for Reithera and is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. G.K. is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders and has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage; has been consulting for Reithera; is on the Board of Directors of the Bristol Myers Squibb Foundation France, and is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. G.K.’s wife, Laurence Zitvogel has held research contracts with 9 Meters Biopharma, Daiichi Sankyo, Pilege, was on the on the Board of Directors of Transgene, is a co-founder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. G.K.’s brother, Romano Kroemer, was an employee of Sanofi and has consulted for Boehringer-Ingelheim. None of the funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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This is excerpted from the Cell 186, January 19, 2023 by Wound World.