.Thoughts & Opinion E. Gilson and T. C. G. Bosch

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Understanding why we age and how:Evolutionary biology meets differentmodel organisms and multi-level omics

Meeting report on “Comparative Biology of Aging,” Roscoff, October 12–16, 2015

Eric Gilson1)2)* and Thomas C. G. Bosch3)*

Aging is ordinarily recognized as aprocess that results from the combinedinfluence of genetic and epigeneticdeterminants, life-style associatedfactors and external events. Studiesusing model organisms such as bud-ding and fission yeasts, the nematodeCaenorhabditis elegans, zebrafish, andmice have generated significant insightinto (epi)genetic pathways involved inaging [1]. However, developing anintegrated understanding of these di-verse processes and, thereby, achievinginsight into the causes and mecha-nisms of the aging process, remain achallenge.

Currently, more and more speciesof exceptional biogerontological inter-est are being discovered [2]. “Multi-level omics” has led to the publicationof nearly complete genotypes, pheno-typic descriptions, and accurate phy-logenetic relationships for thesespecies. To provide a discussion forumfor the experts involved, an interna-tional 2015 meeting on the “Compara-tive Biology of Aging,” hosted by theJacques Monod Conference in Roscoff(Brittany, France) and organized bythe authors, included not only molec-ular cell biologists but also clinicians,

DOI 10.1002/bies.201600049

1) Faculty of Medicine, Institute for Research onCancer and Aging, Nice (IRCAN) University ofNice—Sophia-Antipolis—CNRS UMR 7284-INSERM U1081, 28 Nice, France

2) Department of Genetics, CHU of Nice, Nice,France

3) Zoological Institute, University of Kiel, Kiel,Germany

*Corresponding authors:Eric Gilson and Thomas C. G. BoschE-mail: Eric.Gilson@unice.fr (E.G.) andtbosch@zoologie.uni-kiel.de (T.C.G.B.)

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evolutionary biologists, ecophysiolo-gists, mathematicians, and demogra-phers. Approximately 80 researchersfrom 15 countries gathered in Roscoffto share their work on aging. Theparticipants left the meeting con-vinced that a “Comparative Biologyof Aging 2.0” is on its way.

The molding ofevolutionary theoriesof aging

The conference started by a keynotelecture by Tom Kirkwood (Newcastle),father of the disposable soma theory ofaging [3]. Kirkwood is currently explor-ing life-history evolution (e.g. the evo-lution of menopause) and the optimalallocation of metabolic resources invarying environments (e.g. life exten-sion through rodent calorie-restriction).Such models recently led to the firstevidence for a trade-off between humanlongevity and fertility.

ThedemographerAnnetteBaudisch(Odense) addressed the questions ofhow and why the lifespans of closelyrelated species vary, and the relevanceof this phenomenon to human ageing.Baudisch showed that recent develop-ments in evolutionary biodemographyoffer new theories, methods, and datathat have resulted in striking findingson the diversity of life histories(including, for some species, theability to avoid aging) [4]. As humanlives are rapidly changing owing tounimpeded population aging, thedevelopment of biodemographic theo-ries, methods, and databases mayprove useful and inspire sociologicalprogress.

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Advances in non-modelorganisms

There is a growing recognition of theimportance of non-model organisms inaging research. These non-model crea-tures reveal the highly heterogeneousnature of the aging process, from themandatory aging in bacteria and eukar-yotes that divide by fission to slow-aging organisms such as the nakedmolerat and those exhibiting seeminglyunlimited lifespans (Hydra). How doesNature change the lifespan of species?VadimGladyshev (Boston) approachesthe molecular basis for natural changesin longevity by identifying adaptationsin long-lived mammals and examininglongevity-associated processes acrossall mammals. His lab recentlysequenced and analyzed the genomesof the naked mole rat and Brandt’s bat,as well as a number of other mammalswith exceptional lifespans, and uncov-ered several underlying adaptations.The Gladyshev lab also identified gen-eral gene expression and metabolicchanges—both common strategies suchas nutrient sensing pathways and“private mechanisms,” i.e. lineage spe-cific pathways—that are associated withlonger life, suggesting that these lon-gevity patterns may allow lifespan to beincreased in any mammal species.Naked mole rats are small, hairless,subterranean rodents that are notknown to get cancer despite having a30-year lifespan (see Fig. 1B). Thislifespan is �10-fold longer than thatof the similarly-sized mouse. Along withits longevity, the naked mole rat boastsan array of characteristics that hasmadeit, despite its unimpressive appearance,a darling of medical researchers. It can

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Figure 1. Animal species of biogerontological interest highlighting different focus areas ofthe meeting. A: Young, middle-aged, and old zebra finches, display obvious age-relatedchanges in coloration and condition (image courtesy of Pat Monaghan). B: Naked mole-ratsare the longest-living (>28.3 years) rodents known (image courtesy of Andrei Seluanov andVera Gorbunova, University of Rochester). C: The sea anemone Nematostella vectensis, anemerging model to study extreme regeneration (image courtesy of Eric R€ottinger). D: TheAfrican turquoise killifish (Nothobranchius furzeri) is the shortest lived vertebrate species bredin captivity (image courtesy of Wikipedia). E: Acropora sp (coral animal) does not showoutward signs of aging (image courtesy of Aldine Amiel). F: The core network of thegeroconversion signaling as proposed by Loic Verlingue and A. Londono.

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survive in very low-oxygen conditionsthat cripple human brains. Further-more, the species is immune to can-cers—both natural and experimentallyinduced. Research carried out by VeraGorbunova (Rochester) focuses on DNArepair and cancer-resistance in nakedmole rats in order to understand morefully the mechanisms responsible forlongevity. She identified high molecularweight hyaluronan as the chemical that

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triggers the anti-cancer response in thenaked mole rat, and attributes therodent’s longevity to a process thatresults in nearly-perfect proteinsynthesis.

David Miller (Townsville) pre-sented an overview of aging in corals(Fig. 1E), an animal that can live forthousands of years. This, together withthe fact that the coral and vertebrategene repertoires are remarkably similar,

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makes the coral an attractive emergingmodel for aging studies.

The killifish Nothobranchius furzeri(Fig. 1D), which is the shortest livingvertebrate known, was introduced tothe conference participants by KarlLenhardt Rudolph (Jena) and AnneBrunet (Stanford) [5, 6]. This fish is aparticularly attractive model for agingresearch since short- and longer-livedstrains can be crossed and produceviable offspring. Lifespan can be pro-longed by environmental manipula-tions as well as pharmaceutical drugsand tools for genetic manipulation areavailable.

(Epi)genetic determinantsof aging

To what extent does the incrediblediversity of aging strategies result fromadaptation to environmental changes?Heike Gruber (Pl€on) showed that pre-existing genetic diversity in a popula-tion of rotifers allows them to adoptdifferent life-history strategies depend-ing on the supplied energy level.Benjamin Barre (Gianni Liti lab, Nice)and Jerome Salignon (Gael Yvert lab,Lyon) are using the power of yeastgenomics to understand how the envi-ronment impacts the complex geneticarchitecture of aging. Josh Mitteldorf(Cambridge, USA) regards aging as aprogrammed biological process that isselected at the communal level toaccommodate environmental dynamics,reshaping the famous sentence ofDobzhansky: “Nothing in evolutionmakes sense except in the light ofecology.”

What determines the lifespan ofC. elegans? Ivan Matic (Paris) reportedthat C. elegans exhibits high inter-individual variability in lifespan and thatbacteria used as food may play a majorrole in affecting lifespan in isogenicnematode populations. Matic speculatesthat the developmental plasticity ofC. elegans nematodes, which are self-fertilizing homozygous animals thatproduceoffspringwithnegligible geneticvariation, could increase the probabilityof survival in changing environments.

In the non-senescent freshwaterpolyp genus Hydra, one of the classicalmodel systems for evolutionary

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.Thoughts & Opinion E. Gilson and T. C. G. Bosch

developmental biology and regenera-tion, the transcription factor FoxOmodulates both stem cell proliferationand innate immunity [7]. This providesstrong support for the role of FoxO as acritical rate-of-aging regulator. Accord-ing to Thomas Bosch (Kiel), construct-ing a model of how FoxO responds todiverse environmental factors helpscreate a framework for how stem cellfactors might contribute to aging.

New findings in genomestability, chromatin, andtelomeres

DNA damage is recognized as a majorcontributing factor to aging. Among thestresses that trigger cellular senescence,telomere dysfunctionplays aparticularlycritical role, since it behaves as animportant clock that regulates lifespan [8]. Eric Gilson (Nice) presentedvery recent findings that have unmaskedsome of the circuits regulating telomeresignaling, including DNA topology con-trol and genome-wide outcomes of telo-mere dysfunction. Addressing themechanism that maintains telomeres innon-dividing fission yeast cells, VincentG�eli (Marseille) revealed in quiescentcellsbearingshort telomeresnewtypesoftelomere rearrangements that are other-wise counter-selected when cells exitquiescence. Along with this interest ongenome dynamics in post-mitotic cells,BenoitArcangioli (Paris) showed that infission yeast genome size decreasesduring quiescence due to deletions andmutations increase. Jing Ye (Shanghai)revealed a specific role for telomeres inbrain function, a tissue that is mostlypost-mitotic, showing that the contribu-tion of telomere changes to aging doesnot concern only dividing cells. PatMonaghan demonstrated in zebrafinches (see Fig. 1A) not only thatenvironment greatly influences pheno-type and life history but also that stressaffects telomereattrition.Moreover,workon the Atlantic salmon has uncoveredthat telomere loss during growth varieswith the environment and, even moreinterestingly, that social stress can altertelomere dynamics.

A permanent activation of the DNAdamage response (DDR) leads to cellularsenescence that may be involved in

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organismal aging. Bj€orn Schumacher(K€oln) used the nematodemodel to showthat CEP-1/p53 plays a major role inregulating the DNA damage response ingerm cells. His results also delineate aDAF-16/FoxO mediated DNA damagetolerance pathway that maintainsthe growth of somatic tissues despitegenome instability. The longevity assur-ance mechanisms of DAF-16 activitymight antagonize DNA damage-drivengrowth retardation and aging by elevat-ing tolerance towards persistent oraccumulating DNA damage, thus raisingthe threshold when the age-dependentaccumulation of DNA damage leads tofunctional deterioration. DRR not onlychanges gene expression regulation butalso various levels of chromatin organi-zation. Along the same lines, the charac-teristicheterogeneityof theagingprocessis probably directly related to chromatinregulation mechanisms.

Aging, stem cells, andregeneration

Adult stem cells play a key role in tissuerenewal. Their function declines duringaging, suggesting that a functionalreserve of stem cells extends lifespan.Exploring genetic and epigenetic insta-bility in stem cell aging, Karl LenhardtRudolph (Jena) showed that there is aclonal selection of stem cells and shift inthe stem cell pool during aging. Alter-ations in developmental pathways andkey developmental regulators such asHox genes in adult myogenesis lead toimpaired satellite cell functioning.Focusing on recent discoveries in agingpathways that influence the function ofhuman hematopoetic stem cells,Michelle Goodhardt (Paris) showedthat aging is correlated with the forma-tion of heterochromatin, reduced activ-ity of stem cell genes and increasedexpression of lineage-restricted genes.Vincenzo Constanzo (Milano) reportedprogress in identifying so-calledSomatic to Embryonic Transfer Factors(SETRAFs) that are capable to resettingcellular age.

Interestingly, several marine inver-tebrates such as planarians and cni-darians (i.e. Hydra, sea anemones,corals) have extreme regenerativecapacity and extreme longevity. Eric

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R€ottinger (Nice) is studying the marinecnidarian Nematostella vectensis (seeFig. 1C), for which extreme regenera-tion ability appears linked to extremelongevity and non-senescence. Repeti-tive regeneration in Nematostellaadults is nutrition-independent.

Plants are special because of theirindeterminate growth (some perennialplants are among the longest-livingorganisms, with lifespans of over 11,000years), their modular development, andthe fact that in plants there is noseparation of germ line and soma. Whatkeeps the genomes of plants stable forsuch a long time? Karel Riha (Vienna)proposed that the stratification of plantmeristems might decrease mutations byprotecting stem cells from excessiveproliferation.

Energy metabolism/proteostasis

Metabolic signaling pathways, such asthe IIS/TOR signaling network, playmajor roles in aging. Decreasing theactivity of these signals reduces cellularmetabolism while protecting againstoxidative stress and aging. By express-ing in the nematode C. elegans amitochondrial form of an antioxidantprotein fused to a fluorescent moiety,Meng-Qiu Dong (Beijing) serendipi-tously discovered that the rate offluorescent flashes in young animals isnegatively correlated with its life-span [9]. This highlights the view thataging is a programmed process andraises the question of how mitochon-drial activity predicts its overall rate.

In his keynote address, StevenAustad (Birmingham USA) presentedthe observation that misfolded proteinstend to accumulate in aging cells, and arerelated to dysfunction and disease, mostprominently Alzheimer’s. Long-lived spe-cies, therefore, need to keep proteins inthe right conformation with “chaperone”molecules that are particularly effective.Inhis current research,Austad is isolatingand transplanting some of these chaper-onemolecules fromhismenagerie of 500-year-old clams.

In the clinical sphere, Serge Adnot(Cr�eteil) uncovered a link between telo-mere deficiency, the accumulation ofsenescent cells and pulmonary disease,

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opening new avenues in the treatment ofage-related pathologies. Loic Verlingue(A. Londono lab, Paris) showed post-translational regulation of molecularsignaling for geroconversion, a specialtype of senescence that is increased intype 2 diabetes and can be decreased byrapamycin (see Fig. 1F).

Continued momentum in this fieldrequires a careful analysis of both modeland non-model organisms to achieveholistic insight into the mechanisms,physiology, and “raison d’etre” of agingin the living world. If a comparativeanalysis of aging is to realize its fullpotential, it will be necessary to bridgethe gap between biology and ecology-oriented research and to promote inter-disciplinary collaboration. Through suchcollaborative work, we will achievegreater insight into underlying causes

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for variability in aging among closelyrelated species, and thereby develop adeeper understanding of the aging pro-cess in humans.

AcknowledgmentsWe thank Eric Roettinger and VincentG�eli for comments and apologize tothose whose valuable contributions tothe meeting could not be included dueto limited space.

References

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2. Austad SN. 2010. Animal models of reproduc-tive aging: what can they tell us? Ann NY AcadSci 204: 123–6.

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3. Kirkwood TB. 1977. Evolution of ageing.Nature 270: 301–4.

4. Jones OR, Scheuerlein A, Salguero-G�omezR, Camarda CG, et al. 2014. Diversity ofageing across the tree of life. Nature 505:169–73.

5. Valenzano DR, Benayoun BA, Singh PP,Zhang E, et al. 2015. The African turquoisekillifish genome provides insights into evolutionand genetic architecture of lifespan. Cell 163:1539–54.

6. Reichwald K,Petzold A,Koch P,Downie BR,et al. 2015. Insights into sex chromosomeevolution and aging from the genome of ashort-lived fish. Cell 163: 1527–38.

7. Boehm AM, Khalturin K, Anton-Erxleben F,Hemmrich G, et al. 2012. FoxO is a criticalregulator of stem cell maintenance in immortalHydra. Proc Natl Acad Sci USA 109:19697–702.

8. Ye J, Renault VM, Jamet K, Gilson E. 2014.Transcriptional outcome of telomere signalling.Nat Rev Genet 15: 491–503.

9. Shen EZ, Song CQ, Lin Y, WH Zhang, et al.2014. Mitoflash frequency in early adulthoodpredicts lifespan in Caenorhabditis elegans.Nature 508: 128–32.

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