Antoine Lutz
email: antoine.lutz@inserm.fr

Gael Chételat
email: chetelat@cyceron.fr

Fabienne Collette

Olga M Klimecki

Natalie L Marchant

Julie Gonneaud

The protective effect of mindfulness and

Keywords: Alzheimer's disease, Anxiety, Cognition, eudaimonic well-being, Medit-Ageing

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

mechanisms of non-pharmacological interventions including meditation, in the ageing population.

Objectives:

Our main objective is to propose a model that outlines the cumulative impact that practices of mindfulness meditation (MM) and loving-kindness and compassion meditation (LKCM) (Table 1) could have on cognition, mental health, lifestyle, and AD risk in the ageing population. Drawing on previous research with younger adults, the proposed model aims to function as a heuristic tool to illustrate the putative cognitive, neuroscientific and biological mechanisms of meditation training in ageing. We hope that this framework will stimulate and structure research in this area to support the integration of meditation in non-pharmacological preventive approaches against AD.

3. Background: a. Historical evolution Over the last 20 years, evidence has accumulated towards demonstrating the significant influence of environmental factors, including modifiable lifestyle risk factors, on the development of Alzheimer's disease [START_REF] Norton | Potential for primary prevention of Alzheimer's disease: an analysis of population-based data[END_REF][START_REF] Yegambaram | Role of environmental contaminants in the etiology of Alzheimer's disease: a review[END_REF].

The main modifiable risk factors identified to date include low education, smoking, physical inactivity, depression, mid-life hypertension, diabetes and mid-life obesity [START_REF] Norton | Potential for primary prevention of Alzheimer's disease: an analysis of population-based data[END_REF]. The most relevant in late life are smoking, depression, physical inactivity, social isolation, and diabetes [START_REF] Montero-Odasso | One third of dementia cases can be prevented within the next 25 years by tackling risk factors. The case "for" and "against[END_REF]. There is also evidence for other potentially modifiable risk factors in older adults, including hearing loss, diet, anxiety, neuroticism, rumination, repetitive negative thinking and sleep disorders [START_REF] Marchant | Repetitive negative thinking is associated with amyloid, tau, and cognitive decline[END_REF][START_REF] Marchant | Cognitive Debt and Alzheimer's disease[END_REF][START_REF] Montero-Odasso | One third of dementia cases can be prevented within the next 25 years by tackling risk factors. The case "for" and "against[END_REF][START_REF] Zufferey | Neuroticism, depression, and anxiety traits exacerbate the state of cognitive impairment and hippocampal vulnerability to Alzheimer's disease[END_REF]. Studies showed that 30 to 40% of dementia cases -of which AD is the primary cause -are due to modifiable risk factors [START_REF] Montero-Odasso | One third of dementia cases can be prevented within the next 25 years by tackling risk factors. The case "for" and "against[END_REF][START_REF] Norton | Potential for primary prevention of Alzheimer's disease: an analysis of population-based data[END_REF]. This suggests that a reduction of modifiable risk factors, and possibly the promotion of protective factors, also constitutes a powerful lever towards primary and secondary prevention and reduction of AD cases. Estimation of the possible impact of interventions designed to modify these risk factors are very encouraging, showing that a reduction of 20% per decade in the prevalence of the main risk factors might reduce the number of AD cases in 2050 by 15.3% worldwide, i.e. 16.2 million fewer cases [START_REF] Norton | Potential for primary prevention of Alzheimer's disease: an analysis of population-based data[END_REF]. Multi-target pharmacological trials and lifestyle-based non-pharmacological interventions (and possibly the combination of both) thus represent our best hope to target several of the possible pathways of the disease. Even when a disease-modifying treatment becomes available, the mechanistic understanding of prevention-based reduction of AD risk factors will still be needed.

b. Rationale

The concept of reserve was the first step towards integrating our knowledge on the impact of lifestyle on the physiopathology of the disease [START_REF] Scarmeas | Cognitive reserve and lifestyle[END_REF]. This concept accounts for individual differences in susceptibility to age-related brain changes or AD-related pathology. It proposes notably that a set of life experiences, such as higher educational or occupational attainment, allows some people to cope better than others with brain damage. This concept has stimulated research since the 1990s, and has progressively broadened to include other aspects of life experience such as physical activity, regulation of vascular risk factors, diet, and social stimulation.

Following this line of evidence, non-pharmacological lifestyle-based clinical trials were designed to target one or several risk factors simultaneously. Thus, the three largest multi-domain randomized controlled trials to date (FINGER, PreDIVA and MAPT) [START_REF] Carrié | Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial)[END_REF][START_REF] Kivipelto | The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): Study design and progress[END_REF][START_REF] Richard | Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress[END_REF] incorporated several of the following interventions simultaneously: nutritional guidance, management of metabolic and vascular risk factors, physical exercise, social activities, and cognitive training [START_REF] Carrié | Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial)[END_REF][START_REF] Kivipelto | The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): Study design and progress[END_REF][START_REF] Richard | Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress[END_REF]. Findings from the FINGER study were particularly encouraging, showing for instance a positive effect of the multi-domain intervention on cognitive functions, and on mitigating the dementia risk as measured by an improvement on the "LIfestyle for BRAin Health" (LIBRA) score [START_REF] Ngandu | A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial[END_REF][START_REF] Deckers | Quantifying dementia prevention potential in the FINGER randomized controlled trial using the LIBRA prevention index[END_REF]. These demonstrated proof-of-concepts led to the expansion of the project into a worldwide consortium, called World Wide FINGER. This consortium includes the U.S. POINTER (https://alz.org/us-pointer/), which is a replication study in the US. Noticeably, these interventions targeted all the main risk factors described above with the exception of psycho-affective risk factors, including depression, anxiety, neuroticism, rumination, repetitive negative thinking, which are the focus of the present model.

New or updated hypothesis a. Meditation and ageing: early observational data

We and others have already hypothesized that the sustained and regular practice of mindfulness meditation (MM) can positively affect ageing by improving mental health and well-being and by reducing AD risk ( [START_REF] Acevedo | The Neural Mechanisms of Meditative Practices: Novel Approaches for Healthy Aging[END_REF][START_REF] Chételat | Why could meditation practice help promote mental health and well-being in aging?[END_REF][START_REF] Fountain-Zaragoza | Mindfulness Training for Healthy Aging: Impact on Attention, Well-Being, and Inflammation[END_REF][START_REF] Innes | Meditation as a Therapeutic Intervention for Adults at Risk for Alzheimer†TM s Disease â€" Potential Benefits and Underlying Mechanisms[END_REF][START_REF] Kurth | Promising Links between Meditation and Reduced (Brain) Aging: An Attempt to Bridge Some Gaps between the Alleged Fountain of Youth and the Youth of the Field[END_REF][START_REF] Malinowski | Meditation and Cognitive Ageing: the Role of Mindfulness Meditation in Building Cognitive Reserve[END_REF]). MM primarily develops attention regulation, and meta-cognitive and interoceptive capacities to monitor and regulate emotions, particularly by deconstructing negative automatic mental schemes and fostering emotional balance (e.g. [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF], see Figure 1 and Table 1).

MM can foster lifestyle medicine and health behavior changes by strengthening 1) awareness of unhealthy behaviors, 2) cognitive control of automatic stress reactions that reinforce habits (e.g., inactivity, overeating), and 3) the ability to make healthier choices and sustain behavior change [START_REF] Schuman-Olivier | Mindfulness and Behavior Change[END_REF][START_REF] Victorson | Mindfulness Meditation to Promote Wellness and Manage Chronic Disease: A Systematic Review and Meta-Analysis of Mindfulness-Based Randomized Controlled Trials Relevant to Lifestyle Medicine[END_REF]. Using MM-based intervention is acceptable, feasible, and in-demand for older adults with or without cognitive decline [START_REF] Berk | Can mindfulness-based interventions influence cognitive functioning in older adults? A review and considerations for future research[END_REF][START_REF] Geiger | Mindfulness-Based Interventions for Older Adults: a Review of the Effects on Physical and Emotional Well-Being[END_REF][START_REF] Lenze | Mindfulness-based stress reduction for older adults with worry symptoms and co-occurring cognitive dysfunction[END_REF]. MM-related attention training is thought to exhibit high transfer capacity to other attentional cognitive processes and daily situations, making it a promising technique for AD prevention programs [START_REF] Malinowski | Meditation and Cognitive Ageing: the Role of Mindfulness Meditation in Building Cognitive Reserve[END_REF]. In these proposals, MM is typically thought to impact ageing by strengthening attentional processes, positive affects, psychological well-being and sleep quality, while downregulating risk factors such as stress, inflammation and mood disorders (Figure 2).

For some authors, the slowing down of age-related cognitive decline would be particularly relevant at earlier life stages as prevention while the down-reduction of psycho-affective risk factors could be prioritized at a later life stage (Figure 2, [START_REF] Berk | Can mindfulness-based interventions influence cognitive functioning in older adults? A review and considerations for future research[END_REF]. Evidence for these claims are largely based on observational and intervention-based meditation research in young and middle-aged adults. More specifically, these studies show that MM practice improves cognition (mainly attention, but also memory), reduces sleep disorders (including insomnia), stress, anxiety, depression, feelings of loneliness and social exclusion, and cardiovascular risk factors [START_REF] Dimidjian | Prospects for a Clinical Science of Mindfulness-Based Interventions[END_REF][START_REF] Donald | Does your mindfulness benefit others? A systematic review and meta-analysis of the link between mindfulness and prosocial behaviour[END_REF][START_REF] Kim | Impact of Mindfulness Based Stress Reduction Therapy on Myocardial Function and Endothelial Dysfunction in Female Patients with Microvascular Angina[END_REF][START_REF] Lutz | Investigating the phenomenological matrix of mindfulness-related practices from a neurocognitive perspective[END_REF][START_REF] Tang | The neuroscience of mindfulness meditation[END_REF]. Moreover, the effects of meditation on brain structure and function have consistently been reported in young and middle-aged adults, especially in frontal and limbic structures, as well as in the insula [START_REF] Fox | Functional neuroanatomy of meditation: A review and meta-analysis of 78 functional neuroimaging investigations[END_REF](Fox et al., , 2014, p. 201, p. 201) (Figure 3).

Interestingly, these structures are known to be particularly sensitive to ageing and AD.

MM training has also been associated with increased telomerase activity in blood cells [START_REF] Schutte | A meta-analytic review of the effects of mindfulness meditation on telomerase activity[END_REF], and reduced molecular, genetic and epigenetic markers of inflammation [START_REF] Chaix | Epigenetic clock analysis in long-term meditators[END_REF][START_REF] Kaliman | Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators[END_REF]. Preliminary evidence also comes from cross-sectional studies in expert meditators. While reflecting a life-long meditation experience and subject to multiple biases related to the cross-sectional nature of these kinds of studies, findings in elderly expert meditators support the hypothesis that meditation can preserve brain structure and glucose metabolism (e.g. [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Luders | Estimating brain age using high-resolution pattern recognition: Younger brains in long-term meditation practitioners[END_REF]). We showed for instance preserved grey matter volume and/or more glucose metabolism in six older-adult expert meditators compared to 67 age-matched controls in brain regions sensitive to ageing, including ventromedial prefrontal cortex, anterior cingulate cortex, bilateral temporo-parietal junction, insula and posterior cingulate cortex [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF]. Interestingly, most of these regions also showed the strongest age-related decrease from 20 to 87 years in a cohort of 186 controls [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF], and the temporo-parietal and posterior cingulate cortex are known as being the most sensitive brain regions to early AD-related glucose metabolism changes [START_REF] Teipel | Multimodal imaging in Alzheimer's disease: validity and usefulness for early detection[END_REF]. In support of a preventive effect of meditation on cognitive decline in ageing, cross-sectional studies have also found that elderly longterm meditators have higher levels of attention, executive function, and fluid intelligence compared with non-meditators [START_REF] Gard | The potential effects of meditation on age-related cognitive decline: a systematic review[END_REF][START_REF] Prakash | Long-term concentrative meditation and cognitive performance among older adults[END_REF]. There is emerging evidence indicating that mindfulness-based interventions can impact perceived well-being, executive functioning and memory in healthy ageing [START_REF] Moynihan | Mindfulness-based stress reduction for older adults: effects on executive function, frontal alpha asymmetry and immune function[END_REF], and in patients at risk or with AD [START_REF] Quintana-Hernández | Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial[END_REF][START_REF] Smart | Mindfulness Training for Older Adults with Subjective Cognitive Decline: Results from a Pilot Randomized Controlled Trial[END_REF]. One longitudinal study assessing the impact of eight weeks of mindfulnessbased meditation on brain connectivity found that meditation versus relaxation training decreased network connectivity within the default mode network in older adults, which may indicate more efficient cognitive processes [START_REF] Cotier | A longitudinal study of the effect of short-term meditation training on functional network organization of the aging brain[END_REF]. While these findings are encouraging, further randomized control trials with large samples are necessary to confirm that MM training improves cognition and emotion regulation in older adults, and has therefore the potential to promote healthy ageing.

b. The "Medit-Ageing" hypothesis, and the SCD-Well and Age-Well randomized controlled trials

We further refine and update these early proposals on MM and ageing in two ways.

Firstly, we propose to integrate LKCM in the model. Compared to MM, LKCM is thought to primarily engage perspective taking, empathy and cognitive reappraisal to strengthen motivational processes and to stimulate and reinforce automatic positive schemes involved in caring and pro-social behaviors [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Singer | Empathy and compassion[END_REF] (Figure 1, Table 1). We argue that the combination of both MM and LKCM within a single intervention could optimize the transformative effects of meditation interventions on ageing. Secondly, we advocate for the need to investigate interventions across a longer timescale than the standard 8-week meditation intervention in order to characterize effects on the biology of ageing. We finally illustrate this model with the Medit-Ageing study, an ongoing European study of meditation and ageing.

Our proposal to integrate and combine LKCM with MM is consistent with traditional models of meditation training, and of contemporary LKCM-based interventions, which often start with MM before introducing LKCM [START_REF] Singer | Empathy and compassion[END_REF]. It is also congruent with emerging clinical evidence showing a complementary and beneficial role of LKCM-based interventions on anxiety and depression, positive emotions, purpose in life and social support [START_REF] Donald | Does your mindfulness benefit others? A systematic review and meta-analysis of the link between mindfulness and prosocial behaviour[END_REF][START_REF] Fredrickson | Open hearts build lives: positive emotions, induced through loving-kindness meditation, build consequential personal resources[END_REF][START_REF] Graser | Compassion and Loving-Kindness Meditation: An Overview and Prospects for the Application in Clinical Samples[END_REF]. The training in emotional balance is particularly relevant for ageing as purpose in life and personal growth usually decrease with ageing, and high levels of purposeful life engagement predict extended longevity, reduced physiological dysregulation, and gene expression linked to better inflammatory profiles (Ryff et al., 2016, p. 201). In addition, while both LKCM and MM strengthen the capacities to embrace stressors (see Table 1), the emphasis of the others' care and wellness in LKCM training could be particularly relevant to cope with the dyadic stressors for instance between a person diagnosed with a young-onset dementias and a spousal caregiver (see Table 1 and( [START_REF] Bannon | Thematic Analysis of Dyadic Coping in Couples With Young-Onset Dementia[END_REF]). While there is evidence that MM-based interventions train implicitly some processes related to LKCM [START_REF] Donald | Does your mindfulness benefit others? A systematic review and meta-analysis of the link between mindfulness and prosocial behaviour[END_REF], some recent evidence from affective neurosciences argue for supplementing these programs with an explicit training in LKCM. Consistently, training in LKCM and MM within the same participants induces different structural and functional neuroplastic changes [START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF], suggesting different brain mechanisms and, therefore, possibly complementary effects (Figure 3). For instance, LKCM specifically modulates brain regions such as the striatum and medial orbitofrontal cortex during the perception of emotional stimuli [START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF]. LKCM also plays a distinct role in reducing social stress and stress reactivity compared to MM [START_REF] Engert | Specific reduction in cortisol stress reactivity after social but not attention-based mental training[END_REF], suggesting an alternative pathway to regulate stress. However, while clinical interventions promoting more broadly positive psychology in older adults have reported encouraging findings [START_REF] Friedman | Lighten UP! A Community-Based Group Intervention to Promote Eudaimonic Well-Being in Older Adults: A Multi-Site Replication with 6 Month Follow-Up[END_REF], this mechanistic evidence on LKCM is currently only based on young and middle aged adults.

Extending previous proposals on MM, Figure 1 summarizes the complementary but also overlapping cognitive mechanisms likely engaged in MM and LKCM. In the present framework, the common purpose of these practices is to reinforce positive psychological functioning and eudaimonic well-being [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF]. The common overlapping mechanisms include attention control and meta-awareness. In addition, MM specifically down-regulates maladaptive patterns of thinking or emotional reactivity involved in the escalation of negative mood by learning to engage flexibly with different interpretations of the mental events (see Table 1 for an illustrative example of these concepts and [START_REF] Lutz | Investigating the phenomenological matrix of mindfulness-related practices from a neurocognitive perspective[END_REF] for review). By contrast, LKCM specifically upregulates positive emotions by explicitly cultivating caring, benevolence and pro-social habits. Training these capacities would recruit underlying brain structure and function, especially in frontal and limbic areas [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Functional neuroanatomy of meditation: A review and meta-analysis of 78 functional neuroimaging investigations[END_REF][START_REF] Singer | Empathy and compassion[END_REF] (see Figure 3). It would also downregulate brain network interactions, connectivity patterns and structural changes previously linked to maladaptive emotional states such as chronic stress and depression (e.g. on amygdala responsivity [START_REF] Kral | Impact of short-and long-term mindfulness meditation training on amygdala reactivity to emotional stimuli[END_REF]).

Finally, we hypothesize that these psychological, cognitive, behavioral and brain changes can strengthen protective factors and downregulate detrimental factors of ageing (Figure 2). The specific modulatory effects of MM and LKCM on these processes are not currently known. The positive and negative factors listed in Figure 2 likely exhibit recursive relationships between psychological and biological factors at multiple levels (genes, cells, neural circuits, physiology), which would span over multiple time-scales.

For this reason, in the second aspect of our proposal, we further advocate for the need to investigate meditation interventions at multiple time-scales, spanning across several years, to detect the modulatory effect of meditation on the biological, behavioral and neural markers of ageing. The field of meditation research has almost exclusively focused on short 8-week interventions (with rare exceptions, such as the ReSource project, proposing a 9-month meditation intervention [START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF]). Little is known about the chronometry or time scale of responses to meditation practice, but there is some evidence that some of these effects require sufficient amounts of training to be noticeable. For instance, less amygdala reactivity has been reported in experienced meditators while no such reduction was observed in participants who received a standard 8-week MM-based intervention [START_REF] Kral | Impact of short-and long-term mindfulness meditation training on amygdala reactivity to emotional stimuli[END_REF]. Theoretical models of meditation practices predict an "upward spiral" trajectory of development, where there is a mutual reinforcement between various protective factors of well-being [START_REF] Barnhofer | Mindfulness training in the treatment of persistent depression: can it help to reverse maladaptive plasticity?[END_REF][START_REF] Garland | Upward Spirals of Mindfulness and Reappraisal: Testing the Mindfulness-to-Meaning Theory with Autoregressive Latent Trajectory Modeling[END_REF]. Such a dynamic perspective on meditation training predicts both an accumulating effect of meditation practice, but also some non-linear interactions among these various factors. Sampling multiple time scales is critical to describe the complex dynamic of these psychological, neural and biological changes in response to meditation practice. Here we specifically hypothesize a cascading effect starting by meditation-related changes in psychological processes, which could then impact affective and cognitive risk factors, then biological risk factors, and then gradually altering ageing-related processes (Figure 2). and Table 1). Our cascading hypothesis (see above) predicts that the 8-week SCD-Well intervention should primarily impact the regulation of specific psycho-affective and cognitive processes, with change in anxiety symptoms as the primary study outcome.

Its aim could be understood as supporting or building resilience, that is to develop patients' skills to cope with stress and adversity, in particular due to concern about cognitive functioning. By contrast the 18-month Age-Well intervention should additionally impact biological and neural processes and the regulation of specific lifestyles, including those associated with AD risk, that would eventually impact protracted ageing processes. Beyond developing resilience, this longer intervention could also develop resistance by inducing long-lasting biological protective effects. Its primary outcomes are objective biomarkers of brain integrity in the anterior insula and cingulate cortices.

The cross-sectional study in experts explores the effect of lifelong meditation practice.

Altogether the Medit-Ageing study provides an opportunity to test the present framework.

Major challenges for the hypothesis

One challenge will remain to test the hypothesis of an added value of combining MM and LKCM compared to MM alone will be to properly power such study. The effect of interindividual variation in the response to these meditation techniques is not currently known, even if preliminary evidence suggests that the responses to MM or LKCM practice can interact with individual characteristics [START_REF] Barnhofer | State Effects of Two Forms of Meditation on Prefrontal EEG Asymmetry in Previously Depressed Individuals[END_REF]. Another challenge concerns the generalizability of the empirical data collected during long meditation interventions. While the absence of attrition in the Age-Well study demonstrates the feasibility of this approach, the demands and the commitments required to take part in such studies are likely to bias the demographic of the sample of participants. More generally, the participants' education, social and religious background is expected to modulate the adherence to the therapeutic rationale of meditation.

Conclusive remarks:

Table 1:

Definition of meditations:

Meditation: Meditation can be understood as a family of complex forms of cognitive and affective mental training cultivated for various ends, in particular to decrease human suffering and to increase well-being and human flourishing. We will focus on mindfulness meditation (MM) and loving-kindness and compassion meditation (LKCM), but other meditation techniques can be studied in relation to ageing. Both practices develop positive functioning and eudaimonic well-being, by opposition to hedonic well-being. Positive functioning includes purposeful engagement in life, realization of personal aptitudes and capacities, and enlightened self-knowledge [START_REF] Ryff | Purposeful Engagement, Healthy Aging, and the Brain[END_REF]. Eudaimonic well-being emphasizes meaning, human potential and self-realization and is defined in terms of the degree to which a person is fully functioning [START_REF] Ryff | Purposeful Engagement, Healthy Aging, and the Brain[END_REF]. Hedonic well-being is defined in terms of pleasure attainment and pain avoidance. The meditation interventions discussed here are secular.

Mindfulness meditation (MM):

Mindfulness, or attentive presence, consists of cultivating a vigilant awareness of one's own thoughts, actions, emotions and motivations. The participant learns to intentionally pay attention to his/her internal or external experiences in the present moment without identifying, being absorbed by these experiences or making any value judgment about them. The aim is that the present moment is lived in a more open and flexible way while being less dominated by mental conditioning that is a source of suffering.

Loving-kindness and compassion meditation (LKCM):

The practice of LKCM aims to cultivate feelings of love or compassion for oneself and others and to be more accepting of emotions such as shame, self-criticism, or anger. Building on the non-judgmental monitoring capacity developed in MM, participants learn to cultivate acceptance and kindness toward oneself, for instance in relation to one's negative thoughts, distractions, difficult emotions, unpleasant physical sensations, and to foster appreciation toward positive qualities of one's mind (joy, contentment, …). The participants can then learn to extend an attitude of care a nd loving-kindness toward their loved ones, toward neutral persons (e.g. strangers), or toward difficult persons, ultimately recognizing that the need for comfort, security, and happiness is shared by all living beings.

Phenomenological illustration of the Medit-Ageing model:

To illustrate the cognitive mechanisms likely engaged in MM and LKCM, let us consider a rumination which arises in the mind of an older adult. It might come with thoughts such as "I feel alone and worthless". When the thought arises and one identifies with it, it can appear to be an accurate description of oneself such that a depressed mood is enhanced or sustained. This affective reactivity further ignites the next negative thought.

Attentional mechanism: To regulate this rumination, the first common mechanism of MM and LKCM is attention regulation and monitoring (Figure 4) which would consist here of becoming aware of one's dementia worry or fear of cognitive decline. Instead of being lost in the thought or emotion, the practitioner can acknowledge the thought or emotion and the associated bodily sensations.

Cultivating such nonreactive observations or discernments provide knowledge about the objects of experience and experience itself, which can then be used in the next step of the meditation.

In the Age-Well meditation intervention, this mechanism is mainly trained with MM-related techniques such as Focused Attention meditation on bodily sensations (e.g., breathing exercises, body scan, walking meditation, laying meditation), on external sensations (e.g., to sounds, visual object, food odors, tastes), on feeling tone and emotions (e.g., during physical pain, fatigue, or the loss of a close one), or on thoughts and with Open Monitoring meditation on spontaneous mental activities (e.g. choiceless awareness meditation). This mechanism is implicitly trained in LKCM while one is focusing one's attention for instance on a loved-one while wishing her/him well.

Deconstructive mechanism [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF]: A second core capacity trained in MM is to phenomenally interpret thoughts, feelings, and perceptions just as mental processes rather than as accurate depictions of reality. This mechanism is known as 'dereification', or 'cognitive defusion', or 'decentering' (for a discussion on the distinction between these constructs see [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF]). This process allows the practitioner to relate flexibly to thoughts without reifying any particular interpretation as the only solution and without feeling emotionally attached or reactive to one particular interpretation (Figure 4,right). At the highest form of dereification, thoughts lose their representational status and are experienced as mere mental events, situated and embodied within a field of sensory, proprioceptive, affective, and somatic feeling tones [START_REF] Lutz | Investigating the phenomenological matrix of mindfulness-related practices from a neurocognitive perspective[END_REF]. In the Age-Well meditation intervention, this mechanism is mainly cultivated with MM-related practices through the cultivation of insights on the automaticity of mind-wandering, on the transient and composite nature of the ageing body, and of thoughts and emotions, on the mental tendency to generalize, time-travel, cognitively fused or reify the contents of experience. These various themes are presented in relation to uncertainties of aging, finitude of life, changes in time perception, and roles/responsibilities during aging, and coping with loss in formal meditation and daily life.

Constructive mechanism: LKCM additionally involves altering the content of thoughts and emotions as opposed to simply observing them in MM. To this end, LKCM uses various reappraisal and perspective taking strategies [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF]. For instance, and in response to the rumination, the practitioner can generate a feeling of altruistic love (wishing well-being) or of compassion (wishing freedom from suffering) toward oneself and others. He/She can also imagine that, by experiencing this particular rumination, his/her experience will release all beings from this particular feeling of being alone and worthless. The reappraising of a negative experience into a meaningful and caring one, can increase positive functioning and decrease maladaptive self-schema [START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF]. In the Age-Well meditation intervention, this mechanism is mainly trained with LKCM-related exercises such as the cultivation of acceptation, appreciation and loving-kindness toward one's mind-wandering episodes, one's physical pain, one's ageing body, one's thoughts and emotions; LKCM is then cultivated for one-self, for a loved one, for a neutral person, a difficult person and for all beings. Again, these exercises are integrated in daily life and in particular with the personal and dyadic challenges of ageing [START_REF] Bannon | Thematic Analysis of Dyadic Coping in Couples With Young-Onset Dementia[END_REF].

Figure 1: Psychological and cognitive mechanisms of MM and LKC meditation practices: MM cultivates the non-reactive monitoring of one's actions, emotions, and thoughts and the flexible regulation of attention and emotions; LKCM cultivates benevolence and care for oneself and for others (see Table 1). The pathway on the right downregulates repetitive negative thinking and afflictive emotions, the one on the left upregulates positive and pro-social states. The states cultivated during these meditation practices influences automatic processes involved in emotional appraisal and autonomic and immune systems.

Figure 2: Mechanisms of action of MM and LKCM meditations on ageing factors: Box 1 illustrates how these meditation practices train particular brain states, which are in turn gradually training specific brain networks (see Figure 3, adapted from [START_REF] Malinowski | Meditation and Cognitive Ageing: the Role of Mindfulness Meditation in Building Cognitive Reserve[END_REF]). These states and trained networks facilitate the monitoring, regulating and updating of automatic afflictive mental patterns, and as such can reduce age-related suffering and enhance resilience and well-being. The box 2 illustrates how the processes could then impact lifestyle factors important in ageing including both upregulation of positive factors (e.g. cognitive and brain reserve, cognitive stimulations, social interactions, well-being, telomere lengths) and down-regulation of negative factors (e.g. cardio-vascular risk factors, depression, chronic stress, anxiety, sleep disturbances, cognitive decline, dementia, frailty, disability). We specifically hypothesize a cascading effect starting by meditation-related changes in psychological processes, which could then impact affective and cognitive risk factors, then biological risk factors, and then gradually altering ageing-related processes. Such a cascading effect across multiple domains and time scales could lead to upward or downward spiral trajectories of ageing. Characterizing the time course of this cascading effect will be important to optimally implement MM-and-LKCM-based interventions for prevention and mental health. Neuroimaging studies can track age-related macroscopic, structural, functional and molecular brain changes. They have shown substantial decreases with age in cerebral volume and glucose metabolism [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Fjell | Structural brain changes in aging: courses, causes and cognitive consequences[END_REF]. These changes are not homogeneous throughout the brain as they predominate in the frontal cortex (1,2) and are also often reported in the anterior cingulate cortex (2,3), insula (4), sensorimotor, and perisylvian regions [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Fjell | Structural brain changes in aging: courses, causes and cognitive consequences[END_REF]. Other parietal (5,6) and temporal (7,8) brain regions, including the hippocampus (8), seem to be involved as well, yet findings are less consistent across studies. Findings on MM and LKCM meditation are based on functional or anatomical neuroimaging studies investigating either MM or LKCM states or the plasticity they induced. The withinsubject functional comparison between MM and LKCM is still largely missing. The most consistent brain regions identified across both practices are the mid and anterior cingulate cortex (3), insula (4), precuneus/posterior cingulate cortex (6), amygdala (9) and prefrontal regions in particular, in functional studies, the orbitofrontal and frontopolar cortex (10) [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF]. While hippocampus (8) is found in MM literature [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF] and parahippocampus (11) in LKCM literature [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF], the unique role of each practice will need further confirmation. These findings are interpreted in relation to their roles of these areas in emotion and attention regulation, interoception and various socio-affective processing [START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF]. Only a few studies directly compared the impact of MM and LKCM on the brain anatomy. One landmark study showed that MM practice specifically thickened the medial PFC (2, in blue), consistent with its role in metacognition, while the practice of LKCM specifically thickened post and precentral gyri (12), inferior frontal gyrus (13) and supramarginal gyri (5) (in yellow), consistent with their role in self/other perspective (Figure created with BioRender.com).

Bibliography:

  While longitudinal research on meditation in the elderly population is still in its infancy, novel interventions, such as the Mindfulness-Based Cognitive Approach for Seniors (MBCAS), have been tailored to the needs of older adults. Like other mindfulness-based programs, the MBCAS program aims to teach older adults to monitor without judgement and to positively cope with their habitual responses and reactions to various emotions and stressors. Yet, this program has specifically adapted the mindfulness exercises to the physical and psychosocial challenges related to aging (Zellner Keller et al., 2014).

  The present model and proposals have guided the design of the Medit-Ageing study (public name: Silver Santé Study; www.silversantestudy.eu) which is a European research project focusing on mental health and well-being in ageing populations.Overall, the Medit-Ageing study aims to test the hypothesis that the regular practice of both MM and LKCM in older adults constitutes a protective lifestyle, not only against AD, but also more generally by promoting cognition, mental health, emotional balance, and well-being. It includes two independent clinical studies: SCD-Well and Age-Well. Both constitute a randomized control trial (RCT, ClinicalTrials.gov Identifier: NCT03005652 and NCT02977819), for details see the protocol papers (Poisnel et al., 2018) respectively), while Age-Well additionally includes an observational crosssectional study in older expert long-term meditators (ClinicalTrials.gov Identifier: NCT02977819, (Lutz et al., 2018)). Both interventions used a MM-based intervention that was specifically tailored to the needs of older adults building on modifications suggested by Zellner Keller et al., 2014 together with a particular focus on LKCM. The SCD-Well intervention lasts 8 weeks (2 months) and targets patients suffering from subjective cognitive decline (SCD) where elderly patients experience concerns about cognitive functioning that generates significant emotional difficulties as reflected in persisting symptoms of anxiety and depression. The Age-Well intervention lasts 18 months and targets cognitively unimpaired adults older than 65 years, who have an interest in learning meditation or a foreign language. These two RCTs investigate meditation-related changes at multiple time-scales: for SCD-Well at t0+8 weeks (postintervention) and t0+6 months (4 months post-intervention), and for Age-well at t0+9 months, t0+18 months (post-intervention) and t0+44 months (26 months post-intervention). The meditation interventions aim to train attention and improve cognition, countering stress and improving emotional well-being, and increasing positive psychology, social connectedness and countering feelings of loneliness (Figures 1-2

  Here we introduce a novel model to account for the putative role of meditation training in reducing AD-related risk. We argue that secular meditationbased interventions constitute a promising complementary approach to other preventive strategies by specifically targeting affective risk factors which are known to be impacted by mental training akin to meditation. More specifically, we propose that combining MM and LKCM training during short and long interventions would optimally impact the relevant age-and AD-related factors. The Medit-Ageing study will allow us to start testing this framework. If positive, the long-term goal of this research project will be to provide an evidence-based program containing its active components. Such interventions could be made available to large-scale audiences of older adults as a stand-alone program, or combined with existing multidomain interventions.

Figure 3 :

 3 Figure 3: Schematic view of some of the regions affected by ageing (areas with dashed lines), or recruited or impacted by MM (blue), LKCM (yellow) or both (green).Neuroimaging studies can track age-related macroscopic, structural, functional and molecular brain changes. They have shown substantial decreases with age in cerebral volume and glucose metabolism[START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Fjell | Structural brain changes in aging: courses, causes and cognitive consequences[END_REF]. These changes are not homogeneous throughout the brain as they predominate in the frontal cortex (1,2) and are also often reported in the anterior cingulate cortex (2,3), insula (4), sensorimotor, and perisylvian regions[START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Fjell | Structural brain changes in aging: courses, causes and cognitive consequences[END_REF]. Other parietal (5,6) and temporal (7,8) brain regions, including the hippocampus (8), seem to be involved as well, yet findings are less consistent across studies. Findings on MM and LKCM meditation are based on functional or anatomical neuroimaging studies investigating either MM or LKCM states or the plasticity they induced. The withinsubject functional comparison between MM and LKCM is still largely missing.The most consistent brain regions identified across both practices are the mid and anterior cingulate cortex (3), insula (4), precuneus/posterior cingulate cortex (6), amygdala (9) and prefrontal regions in particular, in functional studies, the orbitofrontal and frontopolar cortex (10)[START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF]. While hippocampus (8) is found in MM literature[START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF] and parahippocampus (11) in LKCM literature[START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF], the unique role of each practice will need further confirmation. These findings are interpreted in relation to their roles of these areas in emotion and attention regulation, interoception and various socio-affective processing[START_REF] Chételat | Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study[END_REF][START_REF] Dahl | Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Klimecki | Functional neural plasticity and associated changes in positive affect after compassion training[END_REF][START_REF] Lutz | Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise[END_REF][START_REF] Valk | Structural plasticity of the social brain: Differential change after socioaffective and cognitive mental training[END_REF]. Only a few studies directly compared the impact of MM and LKCM on the brain anatomy. One landmark study showed that MM practice specifically thickened the medial PFC (2, in blue), consistent with its role in metacognition, while the practice of LKCM specifically thickened post and precentral

Acknowledgments:

We thank two anonymous reviewers who helped to improve this manuscript. The Medit-Ageing project is funded through the European Union in the Horizon 2020 program related to the call PHC22 "Promoting mental well-being in the ageing population." The funder is not involved in the study design, data acquisition, data analysis, data interpretation, or manuscript writing. We thank additional funding from Fondation MMA des Entrepreneurs du futur and the Normandie Région.