Lionel Dahan

Claire Rampon

Cédrick Florian
email: cedrick.florian@univ-tlse3.fr

Age-related memory decline, dysfunction of the hippocampus and therapeutic opportunities

Keywords: aging, hippocampus, synaptic plasticity, adult neurogenesis, epigenetic

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Although the brain retains remarkable plastic abilities in adulthood, aging is classically associated with the deterioration of the individual's physiological and cognitive abilities, and particularly memory. Two types of memories are classically distinguished in mammals: declarative and non-declarative memory [START_REF] Squire | Memory systems of the brain: A brief history and current perspective[END_REF]. Declarative memory concerns the conscious retrieval of facts (semantic memory), events (episodic memory) and perceptual information, whereas non-declarative memory involves the non-conscious recall of motor skills and other tasks, including simple associative and non-associative learning [START_REF] Milner | Cognitive neuroscience and the study of memory[END_REF]. Many studies in humans and rodents have shown that episodic memory and spatial memory, which both depend on the hippocampus, are preferentially affected by aging [START_REF] Bettio | The effects of aging in the hippocampus and cognitive decline[END_REF][START_REF] Erickson | The neurobiology of memory changes in normal aging[END_REF][START_REF] O'shea | Cognitive aging and the hippocampus in older adults[END_REF].

The hippocampus is a brain region that plays a major role in learning and memory in mammals [START_REF] Milner | Disorders of learning and memory after temporal lobe lesions in man[END_REF][START_REF] Zola-Morgan | Human amnesia and the medial temporal region: Enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus[END_REF]. The remarkable structural and functional plasticity of the adult hippocampus provides the fundamental basis for the establishment of long-term memories. Interestingly, the impact of aging on memory may vary greatly among individuals. Many neurobiological mechanisms of cognitive aging have been identified, and deficits in hippocampal plasticity appear to play a major role in age-related decline in cognition both in animals and humans [START_REF] Benayoun | Epigenetic regulation of ageing: Linking environmental inputs to genomic stability[END_REF][START_REF] Bergado | Aging and synaptic plasticity: A review[END_REF][START_REF] Delgado-Morales | Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders[END_REF][START_REF] Katsimpardi | Regulation of neurogenesis in the adult and aging brain[END_REF][START_REF] Lynch | Synaptic plasticity in early aging[END_REF][START_REF] Penner | An epigenetic hypothesis of aging-related cognitive dysfunction[END_REF][START_REF] Sen | Epigenetic Mechanisms of Longevity and Aging[END_REF]. In this review, we focus on hippocampal synaptic plasticity, epigenetic regulation and adult neurogenesis processes that govern memory formation, and we address their modification during aging. We also provide examples of strategies to protect the brain from aging and delay age-related memory decline. The efficacy of these strategies to restore/prevent some of the neurobiological alterations mentioned above has been established in older animals.

Neurobiological mechanisms underlying memory and their vulnerability to aging

The ability to learn and memorize experiences relies on structural and functional modifications of the neuronal brain circuits that can be observed at different levels of brain organization, ranging from synapses to neurons and neuronal networks.

Synaptic plasticity declines with aging

Synaptic plasticity is the process by which the number and strength of connections between neurons can be enhanced or reduced in response to synaptic and neuronal activities. Many types of synaptic plasticity have been described. Among them, long-term potentiation (LTP) and long-term depression (LTD) play crucial roles in learning and memory (for review, see [START_REF] Lynch | Long-Term Potentiation and Memory[END_REF][START_REF] Rosenzweig | Impact of aging on hippocampal function: Plasticity, network dynamics, and cognition[END_REF].

LTP is an increase in glutamatergic synaptic transmission that can be experimentally triggered by high frequency stimulations [START_REF] Bliss | Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path[END_REF]. Suggesting its contribution to memory formation, this phenomenon has also been observed during learning in rodents [START_REF] Broussard | Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus[END_REF][START_REF] Gruart | Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice[END_REF][START_REF] Whitlock | Learning induces long-term potentiation in the hippocampus[END_REF]. The mechanism of LTP is now well described and can be broken down into three consecutive steps : 1/ Induction: LTP is triggered by the flow of Ca 2+ ions into the cell, through Ca 2+ -permeable post-synaptic NMDA receptors [START_REF] Collingridge | Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus[END_REF][START_REF] Lynch | Intracellular injections of EGTA block induction of hippocampal long-term potentiation[END_REF]. 2/ Expression: Calcium influx through the NMDA receptors activates various kinases, such as the CaMKII [START_REF] Malinow | Persistent protein kinase activity underlying long-term potentiation[END_REF] and the PKA [START_REF] Frey | Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons[END_REF], which phosphorylate AMPA receptors [START_REF] Barria | Regulatory Phosphorylation of AMPA-Type Glutamate Receptors by CaM-KII During Long-Term Potentiation[END_REF]. This phosphorylation increases the responsiveness of the postsynaptic element. This LTP expression takes a few minutes to develop and can last for 2 to 4 hours. 3/ Maintenance: In order to make LTP last longer than few hours, kinases allow the expression of immediate early genes such as Zif-268 and Arc, which in turn trigger the synthesis of proteins involved in synaptic transmission and cellular architecture [START_REF] Abraham | Properties and Mechanisms of LTP Maintenance[END_REF][START_REF] Frey | Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation[END_REF][START_REF] Jones | A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories[END_REF]. These proteins are responsible for morphological modifications such as increase in dendritic spine number [START_REF] Yuste | Morphological Changes in Dendritic Spines Associated with Long-Term Synaptic Plasticity[END_REF]. Blocking each step of LTP by pharmacological or genetic tools results in impairments of structural plasticity and in learning and memory deficits [START_REF] Morris | Long-term potentiation and memory[END_REF].

LTP is counterbalanced by an opposite phenomenon called LTD, which reduces the synaptic weight between neurons. LTD can be triggered by NMDA receptors or by metabotropic glutamate receptors and involves the activation of several protein phosphatases (PP1 and PP2A). These enzymes inhibit the kinases implicated in LTP, and dephosphorylate AMPA receptors, thus reducing synaptic transmission [START_REF] Mulkey | Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression[END_REF]. PP1 and PP2A also induce a dephosphorylation of the transcription factor CREB [START_REF] Mauna | Protein phosphatases 1 and 2A are both required for long-term depression and associated dephosphorylation of cAMP response element binding protein in hippocampal area CA1 in vivo[END_REF] and modulate gene expression and protein synthesis and degradation [START_REF] Citri | N -methyl-d-aspartate receptor-and metabotropic glutamate receptor-dependent long-term depression are differentially regulated by the ubiquitin-proteasome system[END_REF][START_REF] Lindecke | Long-term depression activates transcription of immediate early transcription factor genes: involvement of serum response factor/Elk-1[END_REF][START_REF] Manahan-Vaughan | Requirement of translation but not transcription for the maintenance of long-term depression in the CA1 region of freely moving rats[END_REF]. This leads to synapse elimination [START_REF] Bastrikova | Synapse elimination accompanies functional plasticity in hippocampal neurons[END_REF][START_REF] Becker | LTD Induction Causes Morphological Changes of Presynaptic Boutons and Reduces Their Contacts with Spines[END_REF] and spine shrinkage [START_REF] Zhou | Shrinkage of Dendritic Spines Associated with Long-Term Depression of Hippocampal Synapses[END_REF]. Finally, behavioral experiments provide evidence that LTD contributes to forgetting and behavioral flexibility in mice [START_REF] Nicholls | Transgenic Mice Lacking NMDAR-Dependent LTD Exhibit Deficits in Behavioral Flexibility[END_REF].

Interestingly, aging impairs LTP at its induction or at its maintenance and makes LTD easier to trigger and more robust in aged rodents [START_REF] Norris | Increased susceptibility to induction of longterm depression and long-term potentiation reversal during aging[END_REF][START_REF] Rosenzweig | Impact of aging on hippocampal function: Plasticity, network dynamics, and cognition[END_REF]. Although counterintuitive, this can be explained by the differential modulation subunits of NMDA receptors and its consequences on Ca 2+ signaling [START_REF] Kumar | Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence[END_REF]. Indeed, aging is associated with reduced NMDA synaptic transmission caused by a decrease in the number of NMDA receptors and a decrease in the proportion of NR2B subunits, which generally confers a higher Ca 2+ conductance to NMDA receptors [START_REF] Clayton | Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats[END_REF][START_REF] Kumar | Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence[END_REF][START_REF] Magnusson | Age-related changes in the protein expression of subunits of the NMDA receptor[END_REF][START_REF] Sonntag | Age and insulin-like growth factor-1 modulate N-methyl-Daspartate receptor subtype expression in rats[END_REF], eases LTP induction and allows better memory performances [START_REF] Tang | Genetic enhancement of learning and memory in mice[END_REF].

Aging also disrupts neuronal Ca 2+ signaling [START_REF] Foster | Calcium homeostasis and modulation of synaptic plasticity in the aged brain[END_REF][START_REF] Kumar | Susceptibility to calcium dysregulation during brain aging[END_REF][START_REF] Verkhratsky | Calcium and neuronal ageing[END_REF] and disturbs the balance between kinases and phosphatases. This imbalance, by favoring phosphatases responsible for LTD to the detriment of kinases involved in LTP [START_REF] Norris | Alterations in the balance of protein kinase/phosphatase activities parallel reduced synaptic strength during aging[END_REF], might also explain the deleterious effects of aging on synaptic plasticity. Finally, aging also affects hippocampal gene expression, epigenetic modifications and protein synthesis triggered by LTP [START_REF] Ryan | Aging alters long-term potentiation-related gene networks and impairs synaptic protein synthesis in the rat hippocampus[END_REF]. This might contribute to the loss of dendritic spines, without neuronal loss, observed in elderly rats [START_REF] Rapp | Preserved neuron number in the hippocampus of aged rats with spatial learning deficits[END_REF][START_REF] Rasmussen | Memory impaired aged rats: No loss of principal hippocampal and subicular neurons[END_REF][START_REF] West | Regionally specific loss of neurons in the aging human hippocampus[END_REF].

Since NMDA receptors and LTP impairments are correlated to age-related memory deficits [START_REF] Bach | Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway[END_REF] and rescuing NMDA receptors function saves age-related memory deficits [START_REF] Brim | Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor[END_REF], hippocampal synaptic plasticity deficiency has been proposed as a probable cause of memory decline during aging.

Adult hippocampal neurogenesis in the aging brain

Upon experience, the rearrangement of neuronal networks within the brain not only relies on structural plasticity of existing neurons, but also involves the addition of adult-born neurons into existing neuronal circuits. Adult neurogenesis is the process by which new neurons are generated from neural precursors throughout adult life. Adult neural stem cells divide, differentiate through discrete stages of maturation and achieve their functional integration into existing neural networks [START_REF] Gould | Neurogenesis in adult mammals: Some progress and problems[END_REF][START_REF] Ming | ADULT NEUROGENESIS IN THE MAMMALIAN CENTRAL NERVOUS SYSTEM[END_REF]. In the mammalian brain, adult neurogenesis occurs in restricted brain regions including the dentate gyrus of the hippocampus. During their maturation, adult-born neurons go through a critical period during which they are particularly plastic and sensitive to afferent inputs [START_REF] Drew | Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus? Learn[END_REF]. Their singular cellular properties during this critical period give these neurons a particular relevance and make them perfectly adapted to contribute to learning and memory processes. Many experimental studies in rodents have shown that hippocampal-dependent learning modulates adult neurogenesis [START_REF] Gould | Learning enhances adult neurogenesis in the hippocampal formation[END_REF]. Supporting the idea that adultgenerated neurons are causally involved in memory function, we showed that enhancing hippocampal neurogenesis by exposure to an enriched environment is instrumental for the improvement of long-term recognition memory [START_REF] Bruel-Jungerman | New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment[END_REF]. Over the last two decades, the contribution of adult-born granule neurons to the formation of hippocampaldependent memory including flexible learning, spatial memory [START_REF] Petsophonsakul | Memory formation orchestrates the wiring of adult-born hippocampal neurons into brain circuits[END_REF][START_REF] Trouche | Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory[END_REF], pattern separation and encoding of temporal context [START_REF] Sahay | Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation[END_REF] has been well documented in rodents. In line with theoretical approaches, experimental data in rodents and primates support the idea that adult-born neurons contribute to complex behaviors that require distinguishing among similar experiences or resolving memory interference [START_REF] Neunuebel | CA3 retrieves coherent representations from degraded input: Direct evidence for CA3 pattern completion and dentate gyrus pattern separation[END_REF][START_REF] Sakon | A neural signature of pattern separation in the monkey hippocampus[END_REF]. Indeed, manipulating adult-born granule neurons demonstrated that they promote pattern separation, allowing new memories to be encoded, stored and retrieved distinctly from previously encoded similar memories [START_REF] Besnard | Adult Hippocampal Neurogenesis, Fear Generalization, and Stress[END_REF][START_REF] Leutgeb | Pattern separation, pattern completion, and new neuronal codes within a continuous CA3 map[END_REF].

However, an alternative role for adult neurogenesis may also be considered. In 2001, our data led us to believe that adult neurogenesis in the dentate gyrus could represent a powerful mechanism for the periodic elimination of obsolete memory traces from the hippocampus after cortical consolidation. Such a process would allow the hippocampal system to be continuously available to handle new memories [START_REF] Feng | Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces[END_REF]. In line with this idea, computational models predict that high levels of adult neurogenesis, by continuously reshaping the hippocampal networks, lead to the forgetting of established memories [START_REF] Meltzer | A role for circuit homeostasis in adult neurogenesis[END_REF]. In support of this hypothesis, experimental data show that lowering postnatal neurogenesis in mice reduces infantile amnesia, and conversely, that increasing neurogenesis after learning in adult mice promotes forgetting [START_REF] Akers | Hippocampal neurogenesis regulates forgetting during adulthood and infancy[END_REF].

Going even further, recent discoveries reveal that this forgetting is not an erasure, since these memories can be recovered by reactivating the neuronal ensembles activated during the initial encoding [START_REF] Guskjolen | Recovery of "Lost" Infant Memories in Mice[END_REF].

With age, memories become vulnerable, lose their contextual details and become prone to interference suggesting that pattern separation capacities are altered during aging.

Supporting this idea, it is well established that adult hippocampal neurogenesis declines with age, as demonstrated in rodents [START_REF] Demars | Soluble amyloid precursor protein-α rescues age-linked decline in neural progenitor cell proliferation[END_REF], non-human primates [START_REF] Aizawa | Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus[END_REF][START_REF] Leuner | Diminished adult neurogenesis in the marmoset brain precedes old age[END_REF], and humans [START_REF] Bergmann | Adult neurogenesis in humans[END_REF]. Aging is associated with reduced numbers of dividing cells -which become quiescent-and fewer neurogenic precursor cells in the neurogenic brain regions of rodents, non-human primates and humans [START_REF] Aizawa | Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus[END_REF][START_REF] Demars | Soluble amyloid precursor protein-α rescues age-linked decline in neural progenitor cell proliferation[END_REF][START_REF] Encinas | Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus[END_REF][START_REF] Kuhn | Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation[END_REF][START_REF] Spalding | XDynamics of hippocampal neurogenesis in adult humans[END_REF]. Precisely, a massive reduction of the number of proliferating progenitors has been reported [START_REF] Demars | Soluble amyloid precursor protein-α rescues age-linked decline in neural progenitor cell proliferation[END_REF][START_REF] Kuhn | Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation[END_REF], leading to only 25% of proliferative cells at middle to old age compared to numbers at young age in mice [START_REF] Lugert | Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging[END_REF].

Aging is also associated with changes in cell fate choice, with fewer cells adopting a neuronal phenotype and more cells adopting an astrocytic phenotype after exiting the cell cycle [START_REF] Bondolfi | Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice[END_REF][START_REF] Encinas | Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus[END_REF]. Other aspects of the neurogenic process are impaired including cell migration into the granular cell layer and dendritic maturation [START_REF] Rao | The window and mechanisms of major agerelated decline in the production of new neurons within the dentate gyrus of the hippocampus[END_REF]. Although less numerous, newly-generated cells reach full morphological development, achieve their neuronal differentiation and functionally integrate the existing hippocampal networks [START_REF] Morgenstern | Newborn granule cells in the ageing dentate gyrus[END_REF]. Several potential causes that may underlie age-related decline in hippocampal neurogenesis have been proposed. These include changes in stem cell intrinsic factors as well as changes in their extrinsic environment.

Using single-cell RNA sequencing, Artegiani and colleagues were able to precisely identify distinct specific cell-types within the hippocampal neurogenic niche and further revealed age-related changes [START_REF] Artegiani | A Single-Cell RNA Sequencing Study Reveals Cellular and Molecular Dynamics of the Hippocampal Neurogenic Niche[END_REF]. While all cell populations found in young mice were also present in the hippocampal niche of old mice, their relative sizes varied with age.

A strong depletion of neural stem cells and neural progenitors was observed in old mice, while conversely, microglial cells and oligodendrocytes progenitor cells became very abundant with age [START_REF] Artegiani | A Single-Cell RNA Sequencing Study Reveals Cellular and Molecular Dynamics of the Hippocampal Neurogenic Niche[END_REF]. However, the molecular profiles of identified cell populations compared at young and old ages uncovered only minor differences. Whether the molecular programs governing neural stem cell state and fate are affected by aging remains to be explored further.

Mitochondrial function is another intrinsic key regulator of adult neurogenesis [START_REF] Arrázola | Mitochondria in Developmental and Adult Neurogenesis[END_REF] in the composition of the neurogenic niche [START_REF] Shetty | Stem/progenitor cell proliferation factors FGF-2, IGF-1, and VEGF exhibit early decline during the course of aging in the hippocampus: Role of astrocytes[END_REF]. While the complex interaction between neurogenic cells and their niche is difficult to study, parabiosis experiments have provided relevant insights. Heterochronic parabiosis which consists in joining together the circulatory systems of an old and a young mouse, demonstrated the existence of circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. For instance, soluble blood-derived factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice [START_REF] Villeda | The ageing systemic milieu negatively regulates neurogenesis and cognitive function[END_REF]. This study indicates that adult neurogenesis requires favourable environment subject to the influence of systemic and microenvironmental factors and age. In line with these data, Kalamakis and collaborators have recently demonstrated that during aging, inflammatory signals and regulation of the Wnt signaling pathways in the ventricular neurogenic niche keep neural stem cells in a quiescent state, and reduce their activation, thus preventing the depletion of stem cell reservoir [START_REF] Kalamakis | Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain[END_REF].

Remarkably, quiescent neural stem cells can be reactivated upon non pharmacological stimulation, such as physical exercise [START_REF] Lugert | Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging[END_REF], indicating that their plasticity is preserved in the aged brain and might be triggered to prevent cognitive decline.

In human, although the existence of adult neurogenesis has long been a matter of debate, a number of studies supports the idea that adult human hippocampus retains the capacity to generate new neurons. In a seminal study using the unambiguous and gold standard cell birth-dating marker bromo-deoxyuridine (BrdU), Eriksson and colleagues revealed the presence of adult-born neurons in the hippocampus of adult cancer patients [START_REF] Eriksson | Neurogenesis in the adult human hippocampus[END_REF]. While conflicting reports about whether adult neurogenesis persists during aging in human have raised much interest [START_REF] Kempermann | Human Adult Neurogenesis: Evidence and Remaining Questions[END_REF], a convincing study using state-of-the art tissue processing methods, recently reported the presence of numerous immature neurons in the dentate gyrus of healthy human subjects [START_REF] Moreno-Jiménez | Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease[END_REF]. Remarkably, aging seemed to exert only a limited effect on the number of these young hippocampal neurons, as revealed in 90 year-old brains [START_REF] Moreno-Jiménez | Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease[END_REF].

Despite aging, the human brain maintains a substantial pool of young neurons, which may be composed of newly generated cells as well as prenatally generated cells that persist in expressing molecules of immaturity. These neural cells represent a reserve that could be harnessed to prevent damage from aging, supporting the idea that new neurons can be used to improve cognitive functions in the aging brain.

Epigenetic regulations underpinning memory are altered by aging

Chromatin remodeling is one of the major mechanisms responsible for regulating gene expression. Two main molecular epigenetic mechanisms are widely studied in both human and rodents: the regulation of chromatin structure by histone post-translational modifications (more particularly, histone acetylation) and DNA methylation. In the nucleus of the cell, the overall level of histone acetylation is maintained by the antagonistic actions of histone acetyltransferases (HAT) and histone deacetylases (HDAC). An increase of histone H3 acetylation has been observed in the hippocampus of mice after contextual fear conditioning, suggesting that the formation of long-term memory is associated with epigenetic marking of the genome [START_REF] Levenson | Regulation of histone acetylation during memory formation in the hippocampus[END_REF]. Moreover, mice with impaired HAT function exhibit deficits in LTP maintenance and long-term memory [START_REF] Alarcón | Chromatin acetylation, memory, and LTP are impaired in CBP+/-mice: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration[END_REF][START_REF] Vecsey | Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation[END_REF][START_REF] Wood | A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes[END_REF]. Similarly, HDAC2 knockout mice show enhanced memory correlated with increased hippocampal histone H4 acetylation [START_REF] Guan | HDAC2 negatively regulates memory formation and synaptic plasticity[END_REF].

As previously mentioned, memory relies on synaptic plasticity which require gene transcription. Confirming the idea that epigenetic mechanisms are deregulated with age (for review, see [START_REF] Sillivan | Neuroepigenetic regulation of pathogenic memories[END_REF][START_REF] Spiegel | Epigenetic contributions to cognitive aging: Disentangling mindspan and lifespan[END_REF], the transcription of immediate early genes, such as Zif-268, Arc or of neurotrophic factors such as Bdnf, are also affected in old animals [START_REF] Blalock | Gene microarrays in hippocampal aging: Statistical profiling identifies novel processes correlated with cognitive impairment[END_REF][START_REF] Lu | Gene regulation and DNA damage in the ageing human brain[END_REF][START_REF] Penner | An epigenetic hypothesis of aging-related cognitive dysfunction[END_REF][START_REF] Rowe | Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats[END_REF].

Modified histone acetylation associated with aberrant DNA methylation pattern, leads to a difference in gene expression profile that could, in turn, contribute to the progression of agerelated cognitive deficits.

HDAC2 expression is upregulated in the hippocampus of aged mice (Singh andThakur, 2018, 2014). This increase is also correlated with a decline in recognition memory formation.

Overall, several studies showed altered histone proteins during aging. For instance, deregulated histone H4 acetylation in the hippocampus of 16 month-old mice is reported to be responsible for age-associated memory impairment [START_REF] Peleg | Altered histone acetylation is associated with age-dependent memory impairment in mice[END_REF]. In human, increased HDAC1 and HDAC 2 expression is observed in the white matter of elderly donors [START_REF] Gilbert | Neuroepigenetic signatures of age and sex in the living human brain[END_REF].

DNA methylation, driven by DNA methyltransferase (DNMT), consists in the attachment of a methyl group to the CpG dinucleotide sequences. In mammalian cells, DNA methylation is performed by DNMT1 and DNMT3s (DNMT3A and 3B). Several isoforms of DNMT play a role in memory formation [START_REF] Feng | Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons[END_REF]. Genetic or pharmacological inhibition of DNMT impact plasticity and memory formation. Infusions into the hippocampus of the DNMT inhibitors zebularine and 5-aza-2-deoxycytidine (5-aza) affect LTP induction and maintenance [START_REF] Levenson | Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus[END_REF]. Rats exhibit a reduced long-term memory when these DNMT inhibitors are directly injected into the CA1 area of the hippocampus [START_REF] Miller | Covalent Modification of DNA Regulates Memory Formation[END_REF]. Knocking down DNMT3A2 in the adult mouse hippocampus impairs longterm memory formation [START_REF] Oliveira | Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities[END_REF]. Conditional mice with DNMT1 and DNMT3A deletion in the hippocampal CA1 region show abnormal long-term plasticity with deficits in learning and memory [START_REF] Feng | Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons[END_REF]. Taken together, these findings highlight the role of DNA methylation in modulating learning-dependent gene transcription required for long-term memory formation.

DNA hypomethylation appears to be an important feature of aging as well [START_REF] Jones | A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories[END_REF][START_REF] Wilson | Genomic 5-methyldeoxycytidine decreases with age[END_REF] but the causes of such changes in the methylation pattern are still unknown [START_REF] Agrawal | Age-associated epigenetic modifications in human DNA increase its immunogenicity[END_REF][START_REF] Zampieri | Reconfiguration of DNA methylation in aging[END_REF]. Oliveira and colleagues have shown a reduction of DNMTs isoforms in several structures of the aged mouse brain, including the hippocampus [START_REF] Oliveira | Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities[END_REF]. In humans, the comparison of the DNA methylation epigenome in circulating T cells from a newborn and a centenarian has revealed a lower level of methylation of the centenarian's genome compared to newborn's [START_REF] Heyn | Distinct DNA methylomes of newborns and centenarians[END_REF].

This suggests a reduction of the methylome with age. The same conclusion was reached when the level of methylated CpGs nucleotides sequences was compared between hippocampi from juvenile and old mice [START_REF] Liu | Insufficient DNA methylation affects healthy aging and promotes age-related health problems[END_REF]. Conversely, two recent studies focusing on hippocampal mice genome reported a DNA hypermethylation at specific sites with age [START_REF] Hadad | Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation[END_REF][START_REF] Masser | Sexually divergent DNA methylation patterns with hippocampal aging[END_REF]. Finally, epigenetic clocks, which measure DNA methylation pattern (hypo-and hypermethylation) in different sites of the genome, have been reported as potential biomarkers of chronological aging in a wide variety of species, including humans [START_REF] Horvath | DNA methylation-based biomarkers and the epigenetic clock theory of ageing[END_REF][START_REF] Unnikrishnan | The role of DNA methylation in epigenetics of aging[END_REF]). Horvath 's epigenetic clock is considered as the "true" cellular age [START_REF] Horvath | DNA methylation age of human tissues and cell types[END_REF]. While a dysregulation of this "molecular clock" leads to age acceleration, the understanding of its mechanisms could be useful in slowing down the negative effects of aging on cells.

MicroRNAs (miRNAs) represent another aspect of regulatory information that plays critical roles in brain physiology and neurological disorders [START_REF] Aksoy-Aksel | MicroRNAs and synaptic plasticity-a mutual relationship[END_REF][START_REF] Saab | Neuroepigenetics of memory formation and impairment: The role of microRNAs[END_REF]. These tiny, single-stranded noncoding RNAs form short, imperfect complementary base pairing with cellular mRNAs which in turn trigger translation repression and/or destabilization of the targeted mRNAs [START_REF] Fabian | The mechanics of miRNA-mediated gene silencing: A look under the hood of miRISC[END_REF]. The miRNA pathway ensures regulatory functions in neurogenesis, neuronal differentiation, neuronal survival, synaptic connectivity, plasticity and memory-related-processes [START_REF] Konopka | MicroRNA loss enhances learning and memory in mice[END_REF]. For example, in primary hippocampal and cortical neurons cultures, miR-134 limits dendritic spine growth [START_REF] Bicker | The DEAH-box helicase DHX36 mediates dendritic localization of the neuronal precursor-microRNA-134[END_REF][START_REF] Schratt | A brain-specific microRNA regulates dendritic spine development[END_REF]. It also promotes activitydependent dendritogenesis and contributes to homeostatic synaptic depression [START_REF] Fiore | Mi R -134-dependent regulation of P umilio-2 is necessary for homeostatic synaptic depression[END_REF][START_REF] Fiore | Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels[END_REF]. However, expression of miR-134 or its knock-down does not impair memory and learning miRNAs expression is known to be affected in aged mice hippocampus [START_REF] Yang | Microarray Analysis of microRNAs Expression Profiles in Adult and Aged Mice Hippocampus[END_REF]. Several miRNAS have been identified in the aging brain as inducing synaptic plasticity and cognition dysfunctions in mice (Danka [START_REF] Mohammed | miR-204 downregulates EphB2 in aging mouse hippocampal neurons[END_REF][START_REF] Harraz | MicroRNA-223 is neuroprotective by targeting glutamate receptors[END_REF] and human [START_REF] Persengiev | The impact of MicroRNAs on brain aging and neurodegeneration[END_REF]. Indeed, Danka and colleagues showed that miR-2014 is upregulated in hippocampal tissues of old compared to young mice. This upregulation in turn reduces the surface expression of the NMDA receptor subunit (Danka [START_REF] Mohammed | miR-204 downregulates EphB2 in aging mouse hippocampal neurons[END_REF]. Overall, epigenetic manipulations open up interesting avenues for the design of therapeutic interventions to counteract aged-related cognitive decline.

We presented accumulative evidence that epigenetic mechanisms drive changes in gene expression. These changes control hippocampal synaptic plasticity and adult neurogenesis, key mechanisms underlying cognitive functions. During aging, dysregulation of these molecular pathways in the hippocampus alters gene expression and hippocampal functions.

In conclusion, cellular and molecular mechanisms underlying hippocampal functions, including synaptic plasticity, adult neurogenesis and epigenetic regulations, must act in concert to maintain a healthy brain, whereas age-related memory deficits are often initiated by the alteration of one a few of these mechanisms.

Strategies to prevent age-related cognitive decline

For long, pharmacological interventions have been proposed to alleviate altered hippocampal functions in normal aging. Strategies targeting epigenetic mechanisms by using HDAC inhibitors have been largely studied [START_REF] Benito | HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models[END_REF][START_REF] Peleg | Altered histone acetylation is associated with age-dependent memory impairment in mice[END_REF] although the influence of pretraining treatment with HDAC inhibitors on age-related hippocampal memory impairment is controverted [START_REF] Castellano | Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging[END_REF]. Non-pharmacological interventions that manipulate living conditions have shown promise in effectively treating age-related hippocampal memory deficits. Among these interventions, the effectiveness of dietary habits and physical activity to protect the brain from the deleterious effects of aging has been well documented [START_REF] Christie | Do lifestyle activities protect against cognitive decline in aging? A review[END_REF].

There is indeed ample evidence that lifestyle acts as a buffer for normal (and pathological) cognitive aging. Lifestyle factors are numerous and the manipulation of one or several of them has proven to be effective to delay or slow down the deleterious effects of aging on cognition in animals as in humans [START_REF] Fontana | Caloric restriction and cellular senescence[END_REF][START_REF] Most | Calorie restriction in humans: An update[END_REF][START_REF] Wahl | Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia[END_REF]. In particular, healthy diet and occupational activities such as physical or intellectual entertainments have been associated with a better capacity to cope with the physiological effects of time or pathological insults. Although the underlying neurobiological mechanisms

are not yet fully identified, we report below recent evidence suggesting that synaptic plasticity, epigenetic regulations or adult neurogenesis may be involved.

Caloric restriction. Caloric restriction, a reduction in food consumption without malnutrition, is known to extend lifespan in many organisms [START_REF] Pifferi | Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies[END_REF][START_REF] Pistell | Age-associated learning and memory deficits in two mouse versions of the stone Tmaze[END_REF][START_REF] Rapp | Preserved neuron number in the hippocampus of aged rats with spatial learning deficits[END_REF]. Lifelong caloric restriction improves memory in aged rodents [START_REF] Pitsikas | Deterioration of spatial and nonspatial reference and working memory in aged rats: Protective effect of life-long calorie restriction[END_REF], an effect that might be caused by the improvement of NMDA receptors and LTP (Karen Eckles-Smith et al., 2000). Diet modulates the epigenome and growing evidence indicates that nutritional changes can modify age-related epigenetic marks [START_REF] Gensous | Age-related DNA methylation changes: Potential impact on skeletal muscle aging in humans[END_REF]. A recent study reveals that DNA methylation drift, defined as the loss of organized DNA methylation pattern, is delayed when mice are submitted to consistent caloric restriction [START_REF] Maegawa | Caloric restriction delays age-related methylation drift[END_REF]. This result is important since DNA methylation drift has been observed during aging (Ciccarone et al., 2018;[START_REF] Unnikrishnan | The role of DNA methylation in epigenetics of aging[END_REF]. It was also proposed that caloric restriction, by attenuating age-related DNA methylation changes in the hippocampus, may exert a neuroprotective action [START_REF] Hadad | Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation[END_REF]. Similarly, Wood and colleagues showed that overexpression of single microRNA (miR 98-3p) during caloric restriction regulates HAT:HDAC homeostasis and increases the expression of neuroprotective genes in the aged rat brain [START_REF] Wood | Transcriptome analysis in calorie-restricted rats implicates epigenetic and post-translational mechanisms in neuroprotection and aging[END_REF].

Interestingly, caloric restriction also promotes adult neurogenesis in aged brains. In rodents, prolonged diet restriction preserves progenitors proliferation in aged mice [START_REF] Park | Calorie restriction alleviates the agerelated decrease in neural progenitor cell division in the aging brain[END_REF] and increases cell survival in the dentate gyrus in comparison with ad libitum fed animals [START_REF] Kumar | Susceptibility to calcium dysregulation during brain aging[END_REF][START_REF] Lee | Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice[END_REF][START_REF] Lee | Dietary restriction increases the number of newly generated neural cells, and BDNF expression, in the dentate gyrus of rats[END_REF]. Beneficial effects of caloric restriction on the number of newly-born hippocampal neurons and performances in long-term fear memory were also reported in aged mice following short periods of caloric restriction [START_REF] Hornsby | Short-term calorie restriction enhances adult hippocampal neurogenesis and remote fear memory in a Ghsr-dependent manner[END_REF]. Lifelong caloric restriction prevents age-related deficits in LTP and in NMDA receptors expression in rats (Eckles-Smith et al., 2000;[START_REF] Hori | Long-term potentiation is lost in aged rats but preserved by calorie restriction[END_REF]. In elderly, caloric restriction was found to improve cognitive functions [START_REF] Witte | Caloric restriction improves memory in elderly humans[END_REF].

Diet. There is overwhelming evidence to suggest that nutrition holds promise as a preventive strategy against cognitive decline. Interestingly in rodents, omega-3 polyunsaturated fatty acids (omega-3 PFA) supplementation reverses age-related hippocampal synaptic plasticity deficits [START_REF] Crespo | Modulation of miRNA expression in aged rat hippocampus by buttermilk and krill oil[END_REF][START_REF] Martin | Long-term potentiation in aged rats is restored when the age-related decrease in polyunsaturated fatty acid concentration is reversed, in[END_REF][START_REF] Mcgahon | Age-related changes in synaptic function: Analysis of the effect of dietary supplementation with ω-3 fatty acids[END_REF] and enhances hippocampal adult neurogenesis [START_REF] Dyall | The role of omega-3 fatty acids in adult hippocampal Neurogenesis[END_REF]. In non-human primates, long-lasting supplementation with omega-3 PFAs is associated with a higher number of newly born neurons in brain areas related to memory and emotions [START_REF] Royo | Effects of n-3 polyunsaturated fatty acid supplementation on cognitive functions, electrocortical activity and neurogenesis in a non-human primate, the grey mouse lemur (Microcebus murinus)[END_REF]. Clinical studies confirmed that omega-3 PFA intake is a good nutraceutical to improve cognition in the elderly [START_REF] Dangour | Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: A randomized, double-blind, controlled trial[END_REF][START_REF] Van De Rest | Effect of fish oil on cognitive performance in older subjects: A randomized, controlled trial[END_REF]. Conversely, depletion in omega-3

PFA was associated with memory deficits and hippocampal plasticity reduction in rodents [START_REF] Fedorova | Omega-3 fatty acids and rodent behavior[END_REF][START_REF] Luchtman | Cognitive enhancement by omega-3 fatty acids from childhood to old age: Findings from animal and clinical studies[END_REF].

The natural dietary polyphenol resveratrol, which is commonly found in red wine, peanuts and berries, is a sirtuin (SIRT) activator. Resveratrol and sirtuin activators have been proposed for the treatment of aging [START_REF] Knutson | Resveratrol and novel potent activators of SIRT1: Effects on aging and age-related diseases[END_REF]. As a deacetylase, SIRT is an enzyme which removes acetyl groups in histones, leading to DNA silencing [START_REF] Imai | Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase[END_REF]. In aged mice, while reduced SIRT1 level, an NAD + -dependent deacetylase, causes physiological dysfunctions, the overexpression of SIRT1 restores these metabolic dysfunctions [START_REF] Satoh | Sirt1 extends life span and delays aging in mice through the regulation of Nk2 Homeobox 1 in the DMH and LH[END_REF]. Similarly, old transgenic mice overexpressing the SIRT1 gene exhibit lower levels of DNA damage, which stands for one of the hallmarks of aging [START_REF] Herranz | Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer[END_REF]. Interestingly, Mitchell and collaborators showed that elderly mice fed a standard diet supplemented by a specific SIRT1 activator display an increased lifetime as well as a better quality of life [START_REF] Mitchell | The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet[END_REF]. Resveratrol is thought to exert beneficial effects on memory and brain aging [START_REF] Agrawal | Age-associated epigenetic modifications in human DNA increase its immunogenicity[END_REF]. It also regulates hippocampal plasticity and enhances learning and memory in both aged rodents [START_REF] Navarro-Cruz | Effect of Chronic Administration of Resveratrol on Cognitive Performance during Aging Process in Rats[END_REF][START_REF]Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway[END_REF] and healthy elderly [START_REF] Huhn | Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults -A randomized controlled trial[END_REF]. For all these reasons, targeting neuronal epigenetic regulations might help counteract age-related memory decline.

Inconsistent results have been reported regarding the effect of resveratrol on hippocampal adult neurogenesis [START_REF] Mandal | Structural Changes and Proapoptotic Peroxidase Activity of Cardiolipin-Bound Mitochondrial Cytochrome c[END_REF][START_REF] Park | Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis[END_REF], raising the possibility that this phenol may act in a dose-dependent and/or age-dependent manner to enhance adult neurogenesis. Supporting this idea, Kumar and colleagues demonstrated that resveratrol has a biphasic effect on neural progenitor cells in the adult brain. While low concentrations of resveratrol stimulate cell proliferation, high concentrations trigger inhibitory effects. It was found that the beneficial action of resveratrol on cell proliferation is mediated by phospho-CREB and SIRT1, respectively implicated in neuronal survival and lifespan extension [START_REF] Kumar | Differential responses of Trans-Resveratrol on proliferation of neural progenitor cells and aged rat hippocampal neurogenesis[END_REF].

Cognitive enrichment. External environmental factors may also contribute to slow down the deleterious effects of age on the brain. In particular, lifetime exposure to educational and occupational activities, or leisure activities late in life have been associated with a better capacity to cope with the physiological effects of time or pathological insults [START_REF] Leon | Environmental enrichment and successful aging[END_REF]. These observations have fostered the concept of cognitive reserve [START_REF] Stern | Cognitive reserve[END_REF] which accounts for individual differences in susceptibility to age-related brain changes. The neurobiological underpinnings of the cognitive reserve are referred to as the cerebral reserve [START_REF] Stern | Cognitive reserve[END_REF]. Cognitive enrichment and occupational attainment have been proposed to preserve hippocampal functions in old age. For example, cognitive enrichment during adulthood dramatically reduces age-related hippocampal memory decline in elderly [START_REF] Bettio | The effects of aging in the hippocampus and cognitive decline[END_REF][START_REF] Fratiglioni | An active and socially integrated lifestyle in late life might protect against dementia[END_REF]. Healthy elderly with higher cognitive reserve show better verbal episodic memory performances [START_REF] Giogkaraki | The role of cognitive reserve in cognitive aging: Results from the neurocognitive study on aging[END_REF]. Both short-and long-term housing in enriched environment conditions have been proposed to modulate hippocampal synaptic plasticity, adult neurogenesis and gene expression in rodents [START_REF] Cortese | Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity[END_REF][START_REF] Hüttenrauch | Effects of long-term environmental enrichment on anxiety, memory, hippocampal plasticity and overall brain gene expression in C57BL6 mice[END_REF][START_REF] Rampon | Effects of environmental enrichment on gene expression in the brain[END_REF][START_REF] Stein | Short-term environmental enrichment enhances synaptic plasticity in hippocampal slices from aged rats[END_REF]. Old rats exposed to an enriched environment exhibit better hippocampal memory performances than rats maintained in standard housing [START_REF] Cortese | Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity[END_REF]. Much other evidence has shown that age-related changes in hippocampal dendritic branching, spine density and hippocampal adult neurogenesis can be attenuated by exposure to enriched environment [START_REF] Mora | Aging, plasticity and environmental enrichment: Structural changes and neurotransmitter dynamics in several areas of the brain[END_REF]. At the molecular level, enriched environment counteracts the age-related DNA methylation changes occurring in the dentate gyrus of old rats [START_REF] Zocher | Early-life environmental enrichment generates persistent individualized behavior in mice[END_REF].

Physical exercise.

A large body of literature reports that physical activity enhances memory in rodents and significantly counteracts cognitive decline during aging. Similar studies in human have suggested a clear effect of physical exercise on aging, but this issue was recently challenged : meta analyses concluded that they were no significant evidence for a beneficial effect of physical exercise a prevention of cognitive decline [START_REF] Livingston | Dementia prevention, intervention, and care[END_REF][START_REF] Voss | Exercise and Hippocampal Memory Systems[END_REF]. Identifying whether and how physical activity can maintain cognition during aging would have an enormous societal and economic impact. These neurobiological mechanisms have started being investigated in aged rodents. A large body of evidence indicates that physical exercise initiates epigenetic changes that in turn, alter chromatin structure and gene expression, resulting in metabolic consequences, including hereditary ones. For instance, exercise affects methylome patterns which in turn prevents cognitive decline observed in aging. Indeed, a single running session decreases DNMTs levels in young adult rats, without any effect in aged animals [START_REF] Elsner | Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: A preliminary study[END_REF]. Exercise and physical activity increase DNA repair and reduce DNA damage both in rodents (Raefsky and Mattson, 2017) and humans [START_REF] Schmidt | Exercise as Gene Therapy: BDNF and DNA Damage Repair[END_REF]. At the cellular level, voluntary and forced running was found to stimulate hippocampal adult neurogenesis in aged rodents [START_REF] Huang | Effects of voluntary wheel-running types on hippocampal neurogenesis and spatial cognition in middle-aged mice[END_REF][START_REF] Vivar | Running changes the brain: The long and the short of it[END_REF] and in human [START_REF] Ma | Physical exercise induces hippocampal neurogenesis and prevents cognitive decline[END_REF]. Notably, exercise also positively influences broad neuronal morphology by increasing the density of dendritic spines in the hippocampus [START_REF] Stranahan | Running induces widespread structural alterations in the hippocampus and entorhinal cortex[END_REF]. These changes also affect adult-born neurons that show accelerated maturation of their dendritic spines after physical activity in young and middle-age mice [START_REF] Beckervordersandforth | Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis[END_REF][START_REF] Zhao | Distinct morphological 47 stages of dentate granule neuron maturation in the adult mouse hippocampus[END_REF]. Interestingly, these exerciseinduced changes were associated with improvement of cognitive functions, especially those relying on adult-born neurons such as pattern separation [START_REF] Sahay | Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation[END_REF]. Functional consequences of physical exercise also include improved LTP and LTD, processes which sustain memory formation [START_REF] Farmer | Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male sprague-dawley rats in vivo[END_REF][START_REF] Kumar | Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology[END_REF][START_REF] O'callaghan | Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampus[END_REF]. The beneficial effect of physical activity on brain function strongly involves the contribution of trophic factors. Among them, BDNF, VEGF and insulin-like growth factor 1 (IGF-1) were reported to mediate their effects through promoting actions on processes such as angiogenesis, adult neurogenesis, synaptic plasticity or neurotransmission [START_REF] Cao | VEGF links hippocampal activity with neurogenesis, learning and memory[END_REF][START_REF] Sleiman | Downstream Consequences of Exercise Through the Action of BDNF[END_REF][START_REF] Van Der Borght | Physical exercise leads to rapid adaptations in hippocampal vasculature: Temporal dynamics and relationship to cell proliferation and neurogenesis[END_REF]. In the future, efforts to understand the long-term impact of physical activity on age-related cognitive decline must become a priority.

Meditation. As physical exercise, meditation and yoga practice have been proposed to preserve cognitive health in older adults (for review, see [START_REF] Christie | Do lifestyle activities protect against cognitive decline in aging? A review[END_REF][START_REF] Gard | Potential self-regulatory mechanisms of yoga for psychological health[END_REF][START_REF] Sperduti | Meditation and successful aging: Can meditative practices counteract age-related cognitive decline?[END_REF]. Structural plasticity changes in the hippocampus have been associated with yoga practice in several studies [START_REF] Froeliger | Neurocognitive correlates of the effects of yoga meditation practice on emotion and cognition: A pilot study[END_REF][START_REF] Villemure | Neuroprotective effects of yoga practice: Age-, experience-, and frequency-dependent plasticity[END_REF]. Understanding about how meditation improves cognitive function in humans might indeed provide insights into the processes underlying successful cognitive aging. For instance, mindfulness meditation increases memory retrieval and theta oscillations in the brain [START_REF] Nyhus | Increases in Theta Oscillatory Activity During Episodic Memory Retrieval Following Mindfulness Meditation Training[END_REF]. Moreover, it was found that meditation promotes gamma oscillations in practitioners of three different meditation traditions [START_REF] Braboszcz | Increased gamma brainwave amplitude compared to control in three different meditation traditions[END_REF].

Using optogenetic tools or a flickering sensory stimulation, Iaccarino and colleagues were able to increase gamma oscillation in specific brain regions of mouse model of Alzheimer's disease, a process which attenuated amyloid load in a mouse model of Alzheimer disease mouse by activating the microglia [START_REF] Iaccarino | Gamma frequency entrainment attenuates amyloid load and modifies microglia[END_REF]. It would be interesting to test whether triggering gamma activity in aging rodents improves cognition. Identifying the mechanisms at the origin of such an effect would likely provide new hypotheses on how meditation acts on cognitive disorders induced by aging.

Conclusion

Healthy aging is associated with cognitive decline, in human as in rodents. This age-related reduction of cognitive capacities relies on cellular, molecular and functional changes occurring over time in the brain. Today, no medication is able to prevent or counteract this natural process but a number of arguments were gathered, indicating that lifestyle can influence the trajectory of these cognitive impairments.

Studies on animal models have revealed robust beneficial effects of enriched environment, physical exercise or diet on cognitive aging. These studies have also allowed the identification of some of the neurobiological mechanisms underpinning cognitive improvements despite aging. These data support the use of non-pharmacological treatments to ease aging. However, we do not yet know to which extent the beneficial effects of lifestyle manipulations are additive. There may be synergic, as well as antagonistic effects of different lifestyle exposures. It is therefore now necessary to study how coupling of these different approaches prevent or reverse cognitive aging and decipher the neurobiological processes at play. As a whole, lifestyle has proven its capacity to profoundly modify cognitive trajectories during aging and efforts aiming at identifying the combinations of environmental factors best suited for improving cognitive aging have to be maintained.

  . Indeed, by regulating cellular metabolism, mitochondria support efficient lineage

	progression	and	morphological	development	of	adult	neural	stem	cells
	(Beckervordersandforth et al., 2017). Remarkably, it was found that impairing mitochondrial

function mimics several features of aging in adult hippocampal neurogenesis. Conversely, the pharmacological enhancement of mitochondrial function rescues age-related neurogenesis impairments

[START_REF] Beckervordersandforth | Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis[END_REF]

. As a whole, these data suggest that mitochondrial dysfunction participates to age-associated deficits of hippocampal neurogenesis and that enhancing mitochondrial function may improve adult neurogenesis during aging.

Adult neurogenesis occurs in local microenvironments that provide permissive cues. Several cell types populate the neurogenic niche, among which astrocytes and microglia show increased activation with age

[START_REF] Rodríguez-Arellano | Astrocytes in physiological aging and Alzheimer's disease[END_REF]

. As a result, the secretion of neurogenic growth factors typically produced by glia, such as fibroblast growth factor 2 (FGF-2) or vascular endothelial growth factor (VEGF) diminish with age, triggering changes

Acknowledgements

The authors greatly thank Drs L Verret and L Mouledous for their critical reading of the manuscript and discussions. This work was supported by the Fondation pour la Recherche sur le Cerveau (FRC) (to CR), Fondation pour la Recherche Médicale (to CR), Fondation Plan Alzheimer (to LD), Agence Nationale pour la Recherche (ANR) (to CR). We apologize to colleagues whose work could not be cited due to space limitations.

Conflict of Interest

The authors declare that no conflict of interest exists.