Aging Clin Exp Res DOI 10.1007/s40520-016-0716-1

ORIGINAL ARTICLE

Rationale for a preliminary operational definition of physical frailty and sarcopenia in the SPRINTT trial Matteo Cesari1,2 · Francesco Landi3 · Riccardo Calvani3 · Antonio Cherubini4 · Mauro Di Bari5,6 · Patrick Kortebein7,8,9 · Susanna Del Signore10 · Regis Le Lain11 · Bruno Vellas1,2 · Marco Pahor12 · Ronenn Roubenoff13 · Roberto Bernabei3 · Emanuele Marzetti3 · For the SPRINTT Consortium

Received: 10 December 2015 / Accepted: 10 October 2016 © Springer International Publishing Switzerland 2017

Abstract  In the present article, the rationale that guided the operationalization of the theoretical concept of physical frailty and sarcopenia (PF&S), the condition of interest for the “Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies” (SPRINTT) trial, is presented. In particular, the decisions lead to the choice of the adopted instruments, and the reasons for setting the relevant thresholds are explained. In SPRINTT, the concept of physical frailty is translated with a Short Physical Performance Battery score of ≥3 and ≤9. Concurrently, sarcopenia is defined according to the recent definitions of low muscle mass proposed by the Foundation for the National Institutes of Health—Sarcopenia Project. Given the preventive purpose of SPRINTT, older persons with mobility disability (operationalized as incapacity to complete a 400-m walk test within 15  min; primary outcome of the trial) at

the baseline are not included within the diagnostic spectrum of PF&S.

* Matteo Cesari [email protected]

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Physical Medicine and Rehabilitation Service, Sacramento VA Medical Center, Sacramento, CA, USA

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Department of Physical Medicine and Rehabilitation, University of California Davis, Sacramento, CA, USA

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Novartis Institutes of Biomedical Research, Cambridge, MA, USA

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Gérontopôle, Centre Hospitalier Universitaire de Toulouse III, Paul Sabatier, 37 Allées Jules Guesde, 31000 Toulouse, France

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Université de Toulouse III Paul Sabatier, Toulouse, France

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Department of Geriatrics, Neurosciences and Orthopedics, Catholic University of the Sacred Heart School of Medicine, Rome, Italy



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Geriatrics and Geriatric Emergency Care, IRCCS-INRCA, Ancona, Italy

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Research Unit of Medicine of Aging, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Division of Geriatric Cardiology and Medicine, Department of Geriatrics and Medicine, Azienda OspedalieroUniversitaria Careggi, Florence, Italy





Keywords  Physical function · Aging · Prevention · Skeletal muscle · Disability

Introduction The “Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies” (SPRINTT) project is conducted under the European Union’s Innovative Medicine’s Initiative (IMI), and will focus on physical frailty and sarcopenia (PF&S) in older persons (http:// www.mysprintt.eu). The project aims to address academic, regulatory, and operational challenges associated with the study of this population in light of new medicinal products

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Bluecompanion LTD, London, UK

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Sanofi R&D, Chilly‑Mazarin, France

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Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA

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Global Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland

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in development to address its substantial unmet medical need [1]. Amongst other important development elements, the project intends to address these issues by reaching a clinical consensus, proposing diagnostic criteria for PF&S, developing a regulatory work-stream, and sponsoring a randomized clinical trial (which will assess the effects of a multicomponent intervention in community-dwelling older persons with PF&S). The trial should allow a clear characterization of the PF&S condition and support the identification of those individuals who may most benefit from future therapeutic interventions to prevent progression to disability. In this paper, we present the rationale for conducting the SPRINTT investigation in the framework of the PF&S operational definition.

Definition of the physical frailty component The Short Physical Performance Battery (SPPB) was developed to objectively measure lower extremity physical performance [2]. It includes three subtests that evaluate standing balance, usual gait speed over a short distance, and the ability to rise from a chair. For the standing balance test, the subject is asked to stand in three increasingly challenging positions for 10 s each: a side-by-side-feet standing position, a semi-tandem position, and a full tandem position. For the gait speed subtest, the subject is asked to walk at his usual pace over a 4-m course, beginning with a stationary start. The faster of the two trials (time in seconds) is subsequently used for the calculation of the summary score. For the chair-stand subtest, the subject is asked to rise and sit from a chair five times as quickly as possible with hands folded across the chest. This performance is expressed as a total time (in seconds) to complete the test. The results of the three timed tasks are scored from 0 (worst performers) to 4 (best performers) according to predetermined cutpoints. The sum of scores from the three subtests generates a summary score of physical performance ranging from 0 (worst performance) to 12 (best performance) [2–4]. The SPPB has been in use for more than 20  years [5], and has been shown to be a strong predictor of major health-related outcomes in the elderly, including disability [2–4, 6], hospitalization [6], institutionalization [3], and mortality [3, 6]. Interestingly, each of its three subtasks provides different information about the physical performance status of the individual (i.e., balance, mobility, and muscle strength) and is an independent predictor of negative outcomes [6, 7]. This implies that (1) the SPPB is indeed a comprehensive measure able to capture the physical function of an older person and (2) analyses aimed at exploring the physical performance domain more or less affected by the SPRINTT multicomponent intervention will be possible.

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Although the SPPB was not originally designed to measure the frailty status (since frailty had not been formally operationalized at that time), it still adequately responds to the need of detecting older persons with an increased vulnerability to stressors and exposed to higher risk of negative health-related events (including disability). In other words, the theoretical concepts underlying the definition of frailty [8–12] may be easily applied to this physical performance measure. In the absence of a clear “gold standard” assessment tool for frailty, it was recently proposed to restrict the focus to the very inner core of the frailty syndrome and to the primary outcome of geriatric medicine: physical function impairment [5]. In fact, the physical domain is considered to be the main core feature of frailty [13]. Given the frequent description of frailty as a pre-disability condition, the assessment of physical performance has become the standard practice during the assessment of this condition. Moreover, physical performance is closely related to sarcopenia (i.e., the age-related skeletal muscle decline), which represents an important contributor to the extreme vulnerability to stressors of the elderly [14]. For this reason, there is increasing consensus around the adoption of physical performance measures (in addition to muscle mass), such as the SPPB for instance [2, 4] to objectively assess the vulnerability of older people to endogenous and exogenous stressors (i.e., frailty) [15]. By convention, an older person with an SPPB score >9 is considered robust [5]. Conversely, a score ≤9 identifies frail individuals and the lower the score the worse the physical performance of the individual. More specifically, an SPPB score ≤7 is commonly used to define a subgroup of particularly frail individuals [16]. In SPRINTT, we are proposing the use of an SPPB score ranging between 3 and 9 inclusive. This will allow excluding from the trial those subjects that are either too robust or too dependent. At the same time, a relevant number of elders within this range of physical performance (i.e., ≥3 to ≤9) still maintain their mobility capacity (variable of primary interest for the SPRINTT trial). In fact, it has been demonstrated that an older person with an SPPB score ≤7 has an age- and gender-adjusted risk of 66% of developing mobility disability (i.e., incident incapacity to complete a 400-m walk test) over the ensuing 3 years [17]. Although still significantly higher than the reference group, in those with an SPPB equal to 8 or 9, the risk is only about 36% [17]. In a similar vein, the decision to exclude individuals with an SPPB score lower than 3 is motivated by the fact that such poor performance is, in general, not compatible with the ability to complete the 400-m walk test (primary endpoint for the SPRINTT trial; see in the following) [17]. Thus, in the SPRINTT trial, the physical frailty domain of the PF&S condition will be translated into an SPPB score ≥3 and ≤9 (Fig.  1). Special attention will be given

Aging Clin Exp Res Fig. 1  PF&S definition proposed in SPRINTT. SPPB short physical performance battery; PF&S physical frailty & sarcopenia

ROBUSTNESS

SPPB ≥10/12 No sarcopenia No mobility disability

Limit posed by the low SPPB impairment (ceiling effect)

Probable few benefits from intervenons against disability

FRAILTY

SPPB between 3/12 and 9/12 Sarcopenia No mobility disability Possible intervenons for PREVENTING disability

PF&S

SPPB <3/12 Sarcopenia (cachexia?) Mobility disability

DISABILITY

to the frailest participants (those with an SPPB score ≤7), because they are more likely to express the largest effect size from the intervention.

Definition of the sarcopenia component The recent reports by the Foundation for the National Institutes of Health (FNIH) initiative [18] have caused a re-evaluation of previously existing operational definitions of sarcopenia that were largely based on expert consensus opinions [19–23]. The new findings of the FNIH were generated through ad hoc analyses of multiple cohort studies of older persons. Through the adoption of Classification and Regression Tree (CaRT) models, the authors tested a wide range of muscle variables and identified those that best predicted mobility disability [24]. The CaRT statistical models not only support the identification of the best predictors of the studied outcome, but also propose the optimal cutpoints for each. In this way, the FNIH reports have provided the variables that best capture muscle mass and strength decline, as well as proposed gender-specific cutpoints. The FNIH initiative deliberately avoided the use of the term “sarcopenia”, and the authors of the reports kept well differentiated the two domains and presented their work as aimed at identifying clinically relevant measures of muscle mass and strength. This represented quite an important step forward compared with the previous consensus papers that were more likely to operationalize the two domains within

Possible intervenons for TREATING disability Exhauson of endogenous reserves for restoring robustness

Limit posed by the mobility disability (floor effect)

the same algorithms. By stating this, we are well aware that sarcopenia still remains a bi-dimensional condition and that both the quantitative (i.e., muscle mass) and qualitative (i.e., muscle strength) domains need to be represented for its proper identification. Previous consensus papers as well as the FNIH reports recommended the use of handgrip strength for the evaluation of muscle strength. In SPRINTT, where physical frailty is already being coded via the assessment of the SPPB, the addition of the handgrip strength parameter to measure the qualitative domain of sarcopenia might be deemed redundant. In fact, the SPPB already contains a subtask of muscle strength (i.e., the chair-stand test), known to be predictive of negative outcomes (including disability) [6]. For this reason, we chose to operationalize the sarcopenia domain of the PF&S condition by only adopting the FNIH recommendation related to the muscle mass quantification. The FNIH project recommended two gender-specific measures to define low muscle (lean) mass [18]. The first (i.e., appendicular lean mass [ALM]-to-body mass index [BMI] ratio, A ­ LMBMI) is recommended by the FNIH project, while the second (i.e., crude ALM) is proposed as an alternative. Given the relevance of the FNIH initiative and the adopted approach, these definitions should be considered the current “best practice” for defining low muscle mass in the elderly. Having chosen to follow the path paved by the FNIH, we have evaluated several approaches including using ­ALMBMI or ALM individually, as well as a combination

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of the two. Several factors were considered in making this decision. Secondary analyses were performed on existing data collected at the Catholic University of the Sacred Heart (Rome, Italy; partner in SPRINTT) from the protocol of a sarcopenia clinical trial. Thirty-seven communitydwelling older persons who fulfilled the criteria for at least one of several sarcopenia definitions (i.e., those proposed by Baumgartner et  al. [25], Janssen et  al. [26], or Newman et al. [27]) represented the sample group. Of note, the FNIH initiative found that the identification of sarcopenic individuals was quite inconsistent utilizing the different sarcopenia definitions (i.e., European Working Group on Sarcopenia in Older People [19], ­ALMBMI [18], ALM [18], Baumgartner et  al. [25], Janssen et  al. [26], and Newman et  al. [27]) [28]. Our results from the secondary analysis indeed showed that the A ­ LMBMI detected more instances of sarcopenia in overweight or obese (by BMI criterion) subjects, whereas this criterion failed to detect more than half (54.1%) of the study participants in whom other criteria were positive; this was especially relevant in subjects with a BMI below 25  kg/m2. Conversely, when utilizing the crude ALM criterion, only 18.9% of the participants included in our sample were not recognized as sarcopenic. The concordance between ALM and ­ALMBMI at detecting sarcopenia was quite low with only six (16.2%) participants defined as sarcopenic according to both of these criteria. Overall, these findings (consistent with the FNIH reports [28]) suggest that ­ALMBMI may represent a more restrictive criterion for eligibility, potentially driving the profile of the recruited participants in the SPRINTT trial towards a “sarcopenic obesity” condition rather than towards one only examining the amount of lean mass. In conclusion, the recommended definition of the FNIH criteria was based on results of predictive models and confirming that adiposity represents a stronger predictor of negative health-related outcomes (including disability) than lean mass in older persons [27, 29–32]. Applying the A ­LMBMI definition may enrich the SPRINTT target population with sarcopenic obese individuals, potentially increasing the statistical power of our future analyses (due to the higher risk of events expected in this subpopulation). On the other hand, sarcopenia in subjects with normal-to-low BMI might more easily remain undetected with this criterion, with several potential drawbacks: 1. The sample might be skewed towards the identification of sarcopenia in subjects with higher body mass (potentially over representing the sarcopenic obesity subtype). This may generate differences across European countries, since the Northern European population tends to be taller and heavier than the Southern European one;

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2. The use of an entry criterion exclusively based on the ­ALMBMI in SPRINTT might reduce our ability to conduct comprehensive pre-planned and post-hoc analyses at the end of the project. In fact, since such a definition tends to exclude participants with low BMI, future analyses might have limitations at exploring the full range of ALM and the full spectrum of sarcopenia (lean vs. obese). Paradoxically, our consortium may find itself capable of providing comprehensive results for ­ALMBMI, but not for ALM itself. At the same time, it must be emphasized that the former (i.e., ­ALMBMI) is the criterion primarily recommended by the FNIH and indeed the one on which the FNIH reports are centred. The crude ALM criterion is simply presented by the FNIH panel as an alternative. Choosing the latter alone might expose the SPRINTT project to the criticism of not having adhered to the strongest evidence. As discussed in the FNIH publications and as our preliminary analyses show, the crude ALM criterion does not even include all the cases identified by the more restrictive ­ALMBMI. In terms of risk exposure for negative health-related outcomes due to the muscle mass component of sarcopenia, the report by McLean et  al. [33] has shown that low ­ALMBMI is significantly associated with incident mobility impairment (defined as a gait speed ≤0.8 m/s) in both men (pooled odds ratio 1.58, 95% confidence interval 1.12–2.22) and women (pooled odds ratio 1.81, 95% confidence interval 1.14–2.87). Incident mobility impairment represents an earlier stage of mobility dysfunction compared with mobility disability (usually occurring when gait speed is slower than 0.6 m/s [34]). This indicates that the proposed muscle mass criterion for sarcopenia ­(ALMBMI) will likely present a stronger association with the SPRINTT primary outcome (i.e., mobility disability), because it is particularly sensitive and predictive. In conclusion, in SPRINTT, it has been agreed to follow the FNIH recommendations for lean mass cutpoints. Thus, each potential participant will be considered “eligible” if presenting with an A ­ LMBMI below the gender-specific FNIH recommended cutpoint. When the ­ALMBMI criterion is not fulfilled, the individual will then be considered by ALM criterion to verify the true absence of a sarcopenic phenotype (Fig.  1). This approach will not only facilitate participant recruitment, but also allow for pre-planned or post-hoc analyses aimed at refining the PF&S operational definition at the end of the SPRINTT project. In fact, the combination of the two FNIH criteria will allow for the recruitment of participants with a sufficiently wide spectrum of body composition profiles. Within this wider range, it will then be possible to identify the individuals that are more or less likely to benefit from the multicomponent intervention.

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Definition of mobility disability Since the primary outcome of the SPRINTT trial will be the prevention of mobility disability (i.e., incapacity to complete a 400-m walk test within 15  min [35–37]), being able to pass this test at the study entry represents a key inclusion criterion in the operationalization of the target condition (i.e., PF&S; Fig.  1). The choice of the 400-m walk test as a measure of the primary outcome in SPRINTT is justified for several reasons. First, this test provides a dichotomous result (i.e., capacity/incapacity to complete the task), which accurately reflects the specific and clinically relevant condition of mobility disability [35–37]. Next, the definition of mobility disability has already been used in prior geriatric clinical trials, in particular the LIFE studies [16, 38]. The clinical rationale behind the choice of the 400-m walk test is that mobility disability represents the first clinically relevant step in the disabling cascade. This also implies a greater sensitivity of the test to interventions. In fact, by focusing on an early stage of disability, it tends to identify persons in whom the condition has not yet become irreversible. It might be argued that the 6-min walk test (6MWT) could serve as well as the 400-m walk test, or perhaps even better due to its more frequent use. However, these two tests look at different aspects of a subject’s function. The 6MWT was designed to stress the cardiorespiratory capacities of the individual to quantify his/her physiological reserves and exercise tolerance; the results indicate the capacity of the subject to cope with challenging and prolonged stressors. Moreover, the 6MWT has no established goal distance (i.e., the subject walks as far as he/ she can) [39]. In contrast, in the 400-m walk test, the individual is asked to cover a predefined distance at his most convenient pace. It is not specifically intended to measure the physiological resistance of the subject, but rather his/her capacity to function (i.e., reach the specific goal of 400 m). The target distance of 400 m was chosen, because this represents about the average distance that a healthy older adult can cover in 6  min [40]. Moreover, 400 m is comparable to a quarter mile, a distance that is commonly used in self-reported measures of mobilityrelated disability [41]. The maximum time allowed for completing the test (i.e., 15  min) was selected, because the resultant gait speed (i.e., 400 m in 15 min = 0.44 m/s) is also strongly associated with mobility disability [34]. It has been demonstrated that the capacity of the 400-m walk test to predict major negative health-related events (including disability and mortality) is independent of comorbidities. At the same time, subjects with a higher burden of comorbidities are more likely to fail the 400-m walk test. This test is indeed crucial and discriminative

for the functional assessment of apparently well-functioning older adults [35–37].

Other considerations regarding the SPRINTT eligibility criteria The selection criteria proposed in SPRINTT are mainly aimed at (1) excluding persons with specific clinical conditions which may render the intervention unsafe (i.e., severe organ system diseases and unstable health status) and (2) avoiding the inclusion of individuals, whose adherence to the protocol might be low due to clinical (e.g., cognitive impairment and chronic dialysis) and/or non-clinical reasons (e.g., plans to relocate out of the study area). Stratification of the randomization is not foreseen with respect to comorbidities, nutritional status, or habitual physical activity. Frailty is a distinct concept from that of comorbidity, although the two conditions do show some overlap. Therefore, the SPRINTT trial participants will be included because of frailty, as defined by physical performance impairment, and not because of specific diseases. At the same time, it is necessary to exclude from the study those individuals presenting with very severe and disabling diseases, incompatible with the SPRINTT intervention due to safety or compliance concerns. In this context, it is also noteworthy that frail older persons often present with multiple and complex diseases, which often interact with one another. Consequently, the identification of a clinical condition as a unique and exclusive cause of PF&S is practically impossible. Furthermore, the complexity of frailty is not captured by the sum of individual diseases. For this reason, the traditional medical focus on disease needs to be replaced in older subjects by the more practical and clinically relevant concept of function [42]. It is the evaluation of eligibility according to the assessment of function rather than by specific diseases that will render the study sample very representative of a “real life” older adult population.

Principle approach for selecting the main SPRINTT eligibility criteria The eligibility criteria adopted for SPRINTT (and the related ranges of risk for PF&S) have been determined to (1) define a population at risk of negative health-related outcomes (in particular, mobility disability) and (2) be sufficiently conservative to allow post-hoc and pre-planned analyses aimed at refining the operational criteria on the basis of the final results. In fact, a gradient is very likely to exist for both variables of interest in the determination of the risk profile for negative outcomes (including disability). This means that the categorization of these continuous

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parameters will require special attention in the evaluation of the results. In the definition of the physical frailty and sarcopenia domains to be adopted in the SPRINTT trial, the consortium has based the choice of variables and their ranges of interest on existing literature (mainly the LIFE study and the FNIH initiative reports). However, in both cases, such choices have been conservatively selected to allow refinement of the final operational definition when the trial results become available. For example, although the LIFE study results suggested a larger effect size of the physical exercise intervention among the frailest (i.e., SPPB ≤7) participants [16], we have decided not to exclude a priori from the SPRINTT project those elders with SPPB equal to 8 or 9. Similarly, the FNIH initiative recommended the use of the ­ALMBMI parameter to measure low muscle mass with the crude ALM as the alternative [18]. In SPRINTT, it has been decided to use both to, again, allow the generation of a wider spectrum of body composition parameters to be later examined in pre-planned and posthoc analyses. That is, the presence of at least one of the two criteria will be sufficient for inclusion in the study.

Conclusions When examining the eligibility criteria proposed for the SPRINTT clinical trial, it becomes evident that the key criteria are represented by the two conditions defining PF&S (i.e., reduced physical performance and low ALM) applied to a non-mobility disabled population. All other eligibility criteria are not particularly selective and rather are intended to ensure the safe and proper conduct of the trial. This implies that the SPPB and the FNIH criteria (in the absence of mobility disability based on the 400-m walk test) will indeed represent the main features of the selected population at baseline. This will make the sample most representative of larger older adult populations. In other words, the SPRINTT trial is designed to recruit a “real life” sample of community-dwelling older persons with a clear unmet clinical need due to the concomitant presence of physical frailty and sarcopenia. By excluding persons with mobility disability (as defined by the inability to independently walk 400  m [35–37]) at the study entry, and including individuals with poor physical performance (low SPPB score [2–4]) and sarcopenia (according to the FNIH criteria [18]), we are confident of selecting a non-disabled population at a particularly high risk of becoming dependent over the short term. Each of the key inclusion criteria singularly represents a strong and independent predictor of negative health-related events (including disability) in older persons. Their combined criteria result in a significantly

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increased risk, and concur to restricting the risk profile to a specific organ (i.e., skeletal muscle). As previously noted, the predictive value of physical performance measures for negative outcomes in the elderly is well established [2–4, 43]. Moreover, most of the instruments specifically assessing frailty already consider physical performance among the key determinants of the syndrome [9, 44]. The assessment of frailty using a “physical parameter” (i.e., SPPB) may also facilitate the identification of individuals at high risk of mobility disability in routine practice, because physical performance measures are easy-to-perform, inexpensive, objective, standardized, repeatable, and highly reliable, even in primary care setting [5, 45]. The criteria we will use to define the sarcopenic domain of PF&S [18] were developed with statistical models using mobility impairment (i.e., slow gait speed) as the outcome of interest [24, 46]. By pooling data from large cohort studies, the FNIH initiative has clearly demonstrated that the proposed variables related to lean mass are strong predictors of an outcome based on gait speed that is consistent with the one we will adopt in SPRINTT and of major interest for geriatric medicine (i.e., mobility impairment). The SPRINTT consortium believes that the SPPB represents the most feasible and objective definition that can be adopted for translating the complex concept of physical frailty into clinical and research practice. At the same time, to our knowledge, the findings from the FNIH initiative provide the most robust evidence-based data allowing the characterization of the sarcopenia phenomenon. Therefore, we believe that by combining these parameters, we will be able to define a population characterized by a particularly high-risk profile for disability outcomes. Finally, the exclusion criteria have been designed to exclude elders with acute or unstable clinical conditions to reduce the risk of treatment-related adverse events, while at the same time ensuring that the studied sample remains representative of elders living in the community. Acknowledgements  The present work was Funded by a Grant from the Innovative Medicines Initiative—Joint Undertaking (IMI-JU 115621). The work was also partly supported by the “Centro Studi Achille e Linda Lorenzon” (E.M., R.C.), Fondazione Roma (NCDs Call for Proposals 2013; E.M., R.C.), and intramural research Grants from the Catholic University of the Sacred Heart (D3.2 2013 and D3.2 2015; E.M., F.L., R.C.). Compliance with ethical standards  Conflict of interest  The authors of the present work are partners of the SPRINTT Consortium, which is partly funded by the European Federation of Pharmaceutical Industries and Associations (EFPIA). E.M. served as a consultant for Huron Consulting Group, Genactis, and Novartis. M.C. served as a consultant for and/or received honoraria for scientific presentations from Nestlé.

Aging Clin Exp Res Ethical approval  This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent  For this type of study, informed consent is not required.

References 1. Marzetti E, Calvani R, Landi F et al (2015) Innovative medicines initiative: The SPRINTT Project. J Frailty. Aging 4:207–208. doi:10.14283/jfa.2015.69 2. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB (1995) Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 332:556–561. doi:10.1056/NEJM199503023320902 3. Guralnik JM, Simonsick EM, Ferrucci L, et  al. (1994) A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol 49: M85–94. doi:10.1093/geronj/49.2.M85 4. Guralnik JM, Ferrucci L, Pieper CF, et al. (2000) Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci 55: M221–31. doi:10.1093/gerona/55.4.M221 5. Studenski S, Perera S, Wallace D et  al (2003) Physical performance measures in the clinical setting. J Am Geriatr Soc 51:314–322. doi:10.1046/j.1532-5415.2003.51104.x 6. Cesari M, Kritchevsky SB, Newman AB et  al (2009) Added value of physical performance measures in predicting adverse health-related events: results from the Health, Aging And Body Composition Study. J Am Geriatr Soc 57:251–259. doi:10.1111/j.1532-5415.2008.02126.x 7. Cesari M, Onder G, Zamboni V et  al (2008) Physical function and self-rated health status as predictors of mortality: results from longitudinal analysis in the ilSIRENTE study. BMC Geriatr 8:34. doi:10.1186/1471-2318-8-34 8. Rodríguez-Mañas L, Féart C, Mann G et al (2012) Searching for an operational definition of frailty: a delphi method based consensus statement. The Frailty Operative Definition-Consensus Conference Project. J Gerontol A Biol Sci Med Sci 68:62–67. doi:10.1093/gerona/gls119 9. Fried LP, Walston J (2003) Frailty and failure to thrieve. In: Hazzard WR, Blass JP, Ettinger WH, Halter JB, Ouslander JG (eds) Principles of Geriatric Medicine and Gerontology. McGraw-Hill, New York, pp 1487–1502 10. Fried LP, Tangen CM, Walston J, et  al. (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56: M146–56. doi:10.1093/gerona/56.3.M146 11. Morley JE (2013) Frailty: a time for action. Eur Geriatr Med 4:215–216. doi:10.1016/j.eurger.2013.08.006 12. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K (2013) Frailty in elderly people. The Lancet 381:752–762. doi:10.1016/ S0140-6736(12)62167-9 13. Ferrucci L, Guralnik JM, Studenski S et  al (2004) Design ing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: a consensus report. J Am Geriatr Soc 52:625–634. doi:10.1111/j.1532-5415.2004.52174.x 14. Cesari M, Landi F, Vellas B, Bernabei R, Marzetti E (2014) Sarcopenia and physical frailty: two sides of the same coin. Front Aging Neurosci 6: 192. doi:10.3389/fnagi.2014.00192

15. Abizanda P, Romero L, Sanchez-Jurado PM et  al (2012) Association between functional assessment instruments and frailty in older adults: the FRADEA study. J Frailty. Aging 1:162–168. doi:10.14283/jfa.2012.25 16. Pahor M, Guralnik JM, Ambrosius WT et  al (2014) Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 311:2387–2396. doi:10.1001/jama.2014.5616 17. Vasunilashorn S, Coppin AK, Patel KV et al (2009) Use of the short physical performance battery score to predict loss of ability to walk 400 meters: analysis from the InCHIANTI study. J Gerontol A Biol Sci Med Sci 64:223–229. doi:10.1093/gerona/ gln022 18. Studenski SA, Peters KW, Alley DE et al (2014) The FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates. J Gerontol A Biol Sci Med Sci 69:547–558. doi:10.1093/gerona/glu010 19. Cruz-Jentoft AJ, Baeyens JP, Bauer JM et al (2010) Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39:412–423. doi:10.1093/ageing/afq034 20. Fielding RA, Vellas B, Evans WJ et  al (2011) Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 12:249–256. doi:10.1016/j.jamda.2011.01.003 21. Muscaritoli M, Anker SD, Argiles J et al (2010) Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr 29:154–159. doi:10.1016/j.clnu.2009.12.004 22. Morley JE, Abbatecola AM, Argiles JM et al (2011) Sarcopenia with limited mobility: an international consensus. J Am Med Dir Assoc 12:403–409. doi:10.1016/j.jamda.2011.04.014 23. Reginster JY, Cooper C, Rizzoli R et  al (2016) Recommendations for the conduct of clinical trials for drugs to treat or prevent sarcopenia. Aging Clin Exp Res 28:47–58. doi:10.1007/ s40520-015-0517-y 24. Cawthon PM, Peters KW, Shardell MD et  al (2014) Cutpoints for low appendicular lean mass that identify older adults with clinically significant weakness. J Gerontol A Biol Sci Med Sci 69:567–575. doi:10.1093/gerona/glu023 25. Baumgartner RN, Koehler KM, Gallagher D et al (1998) Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 147:755–763 26. Janssen I, Heymsfield SB, Ross R (2002) Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 50:889–896. doi:10.1046/j.1532-5415.2002.50216.x 27. Newman AB, Kupelian V, Visser M et  al (2003) Sarco penia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc 51:1602–1609. doi:10.1046/j.1532-5415.2003.51534.x 28. Dam TT, Peters KW, Fragala M et al (2014) An evidence-based comparison of operational criteria for the presence of sarcopenia. J Gerontol A Biol Sci Med Sci 69:584–590. doi:10.1093/gerona/ glu013 29. Newman AB, Kupelian V, Visser M et  al (2006) Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci 61:72–77 30. Newman AB, Haggerty CL, Goodpaster B et al (2003) Strength and muscle quality in a well-functioning cohort of older adults: the Health, Aging and Body Composition Study. J Am Geriatr Soc 51:323–330. doi:10.1046/j.1532-5415.2003.51105.x

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31. Cesari M, Pahor M, Lauretani F et al (2009) Skeletal muscle and mortality results from the InCHIANTI Study. J Gerontol A Biol Sci Med Sci 64:377–384. doi:10.1093/gerona/gln031 32. Visser M, Goodpaster BH, Kritchevsky SB et al (2005) Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci 60:324–333. doi:10.1093/ gerona/60.3.324 33. McLean RR, Shardell MD, Alley DE et  al (2014) Criteria for Clinically Relevant Weakness and Low Lean Mass and Their Longitudinal Association With Incident Mobility Impairment and Mortality: The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. J Gerontol A Biol Sci Med Sci 69:576–583. doi:10.1093/gerona/glu012 34. Rolland YM, Cesari M, Miller ME et  al (2004) Reliability of the 400-m usual-pace walk test as an assessment of mobility limitation in older adults. J Am Geriatr Soc 52:972–976. doi:10.1111/j.1532-5415.2004.52267.x 35. Sayers SP, Guralnik JM, Newman AB, Brach JS, Fielding RA (2006) Concordance and discordance between two measures of lower extremity function: 400  m self-paced walk and SPPB. Aging Clin Exp Res 18:100–106 36. Chang M, Cohen-Mansfield J, Ferrucci L et  al (2004) Inci dence of loss of ability to walk 400 meters in a functionally limited older population. J Am Geriatr Soc 52:2094–2098. doi:10.1111/j.1532-5415.2004.52570.x 37. Rejeski WJ, Fielding RA, Blair SN et  al (2005) The life style interventions and independence for elders (LIFE) pilot study: design and methods. Contemp Clin Trials 26:141–154. doi:10.1016/j.cct.2004.12.005 38. Pahor M, Blair SN, Espeland M et al (2006) Effects of a physical activity intervention on measures of physical performance:

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Aging Clin Exp Res

39. 40.

41. 42. 43.

44.

45. 46.

results of the lifestyle interventions and independence for Elders Pilot (LIFE-P) study. J Gerontol A Biol Sci Med Sci 61:1157–1165 Cesari M, Scarlata S (2014) What the 4-metre gait speed measures and why it cannot replace functional capacity tests. Eur Respir J 43:1819–1820. doi:10.1183/09031936.00207913 Simonsick EM, Montgomery PS, Newman AB, Bauer DC, Harris T (2001) Measuring fitness in healthy older adults: the health ABC long distance corridor walk. J Am Geriatr Soc 49:1544– 1548. doi:10.1046/j.1532-5415.2001.4911247.x Rosow I, Breslau N (1966) A Guttman health scale for the aged. J Gerontol 21:556–559 Cesari M, Vellas B, Gambassi G (2013) The stress of aging. Exp Gerontol 48:451–456. doi:10.1016/j.exger.2012.10.004 Abellan van Kan G, Rolland YM, Andrieu S et  al (2009) Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 13:881–889. doi:10.1007/s12603-009-0246-z Ensrud K, Ewing SK, Taylor BC et  al (2008) Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med 168:382–389. doi:10.1001/archinternmed.2007.113 Cesari M (2011) Role of gait speed in the assessment of older patients. JAMA 305:93–94. doi:10.1001/jama.2010.1970 Alley DE, Shardell MD, Peters KW et  al (2014) Grip strength cutpoints for the identification of clinically relevant weakness. J Gerontol A Biol Sci Med Sci 69:559–566. doi:10.1093/gerona/ glu011