Physical frailty and loss of functional independence in old age : determinants and adaptations to physical activity (BETTER-AGEING)

Deliverables

WP-2 focused on one of the aspects of age induced frailty, i.e. muscle weakness, and analysed its possible causes at cellular and molecular level. In more detail the WP aimed to assess whether muscle weakness is due to: - A shift in fibre type composition and/or a selective fibre atrophy (slow fibres develop less force and much less power than fast fibres); - A decrease in myofibrillar protein content of muscle fibres that exceeds the decrease in CSA determining a decline in myofibrillar protein density: - A change in functional properties of muscle fibres; - The impact of training on single muscle fibre properties in the elderly. The research work has clarified that: - Fibre type composition in elderly subjects is significantly affected by the level of activity going through a shift towards fast fibres in sedentary elderly subjects and towards slow fibres in active elderly subjects; - In elderly subjects a loss of contractility, namely a decrease in force and velocity, occurs in single muscle fibres independently from a change in myosin isoform (fibre type) due both to a loss of myosin, the motor of contraction, in the fibres and to a change in the function of the myosin molecule itself; - A long duration training at moderate intensity is able to increase both force and velocity of muscle fibres independently from a change in fibre type both in young and elderly subjects and is therefore able to counteract the effect of ageing on structure and function of muscle fibres.

Few studies have considered functional ability together with muscle power and community-dwelling elderly as population sample. There are few long-term studies and they mostly involve supervised training, which could reach a limited number of people. Partially supervised, home-based or mixed training programmes could potentially have a larger impact on the elderly population. The aim of this study was to determine to which extent and how differently a long-term mixed strength training programme at moderate intensity can impact on muscle function (MF), functional ability (FA) and physical activity (PA) profile in healthy community-dwelling men and women over 75 years of age. We also wanted to address the relationship of lower extremity strength-power and the ability to accomplish selected functional activities in order to identify the most influencial determinant of performance in old age. Training was performed twice a week in a hospital-based training facility with two multi-gym machines for the lower limbs at 60% of the repetition maximum (1 RM). At home subjects used elastic bands once a week. We measured: maximum isometric strength of knee extensors (KE), ankle plantar flexors (PF), leg extensor power (LEP), Functional reach (FR), Chair rise 1 (CR1) and 10 times (CR10), Bed rise (BR), Six-min walking test (6MWT), Stair climbing (SC), Get up and go (GU&G), One-leg standing (1LS). Physical activity (PA) was assessed with the Paqap questionnaire. Women were significantly weaker than men at baseline: -47% for KE and -59% for PF. Training induced significant gains in MF and FA in the training females; males improved significantly only FA. PA levels increased in the training group. Long-term mixed programmes can improve MF and FA in elderly females and FA in males. The main finding of this study is that a long-term mixed training programme at moderate intensity is effective in improving MF, and FA in healthy elderly women and can positively affect life style. Women represent the first target of training programmes since their muscle power might decline in old age below the threshold needed for basic daily life activities. Muscle power appears therefore a crucial determinant of performance for women, whereas men seem to have �safety margins� of muscle power for daily functional activities. The men probably require intensities of training higher than 60% 1RM to improve MF, but still moderate training has shown to improve their FA and life style. LEP showed higher correlation coefficients than KE-PF with FA: the average correlation coefficient for GU&G, SC, CR10, 6MWT was r= - 0.52 with LEP and r= -0.43 with KE-PF. LEP appears therefore a more relevant measurement than strength to important mobility tasks. FA tests, namely GU&G, SC, CR10 and 6MWT, can be used to reliably assess muscle power capacity in ambulatory care or home setting instead of more expensive instruments.

This study aimed at investigating the alterations in muscle architecture and in tendon mechanical properties associated with old age, their impact on muscle and locomotory function, and their reversal/mitigation in response to a 12-month physical activity programme. The study was performed on 58 older individuals (28 males, 30 females) and compared to those obtained on 31 younger adults (15 males, 16 females). The results obtained showed that sarcopenia is associated with a reduction in fibre fascicle length and pennation angle of the plantarflexor muscles and with lower tendon stiffness in older individuals. Neural drive to the muscle was also different from that of young adults since muscle voluntary activation was found to be lower in the older individuals. The combined effect of these changes accounted for about 50% of the loss in peak muscle power and 70% of the loss in isometric strength, indicating a deterioration in muscle quality in old age. The lower tendon stiffness in the elderly was also reflected by a different behaviour of the fibre fascicles and the tendon throughout the walking cycle: in the older individuals, fascicle length remained more or less constant while the tendon underwent considerable stretch, whereas in the young, greater fascicle and lower tendon length changes were observed. This different behaviour of the muscle-tendon complex of the older individuals was associated with an increased metabolic cost of walking and with a greater antagonist muscle co-activation. In response to the 12-month physical activity programme, a significant reversal of these age-related changes was found since, - Muscle cross-sectional area and volume were larger, - Fascicle length and pennation angle increased, - Tendon stiffness increased, - Voluntary activation was greater, - Both absolute and relative (normalised for muscle CSA and volume) peak isometric force and power increased. Although these adaptations had no effect on the metabolic cost of walking (probably because of insufficient intensity of the aerobic component in the training), these were associated with an improvement in functional performance (6 min walk test, get up and go, one-leg standing balance). These findings indicate that muscle weakness in old age is not only due to a loss of muscle mass (sarcopenia) but also to alterations in the internal architecture of skeletal muscle compounded by a deterioration in tendon stiffness and by changes in neural drive which have repercussions on the metabolic cost of locomotion. However, physical activity based on aerobic, concentric/eccentric strength and proprioceptive exercises performed at least twice per week, proves effective in reversing/mitigating most these age-related changes, resulting in improved muscle quantity, quality and functional performance. Since the strength training protocol used in this study involved several eccentric exercises, it is believed that the muscle stretch caused by this type of contraction provides an important stimulus for restoring muscle mass and fibre fascicle length. Hence it is recommended that future training programmes designed for older individuals should implement eccentric loading in their protocol including, also, aerobic and proprioceptive exercises.

This work package addressed physical activity, psychological well-being, quality of life and links with functionality in the frail elderly. The study provided the largest European data set on objectively measured (accelerometry) physical activity in older people aged 70 and over. This was accompanied by estimates of mental well-being and quality of life through standardised questionnaires. Older people have very low levels of daily activity, particularly at a level of intensity that would improve health. This indicates that there is a lot of scope for programmes and policy designed to enhance walking and other forms of activity. Mental health is weakly and positively related to daily physical activity. Qualitative and quantitative data showed that engagement in the standardised exercise training programme improved aspects of mental well-being. It was seen as a very positive experience by participants. However, we found no evidence that the programme outcomes translated into greater levels of daily activity. Further analyses are currently being conducted as agreed in the initial contract. More research is needed to assess determinants of daily physical activity and physical independence in this population. Results are summarised in a dissemination document made available to leading non governmental and governmental organisations concerned with the health of elderly people.

Neuromuscular plasticity and ageing: Ageing of the motor function is characterized by the decrease in muscle mass and strength. Thus, we evaluated neuromuscular function in older individuals. Maximal torques of lower limbs are particularly affected under isometric and concentric conditions. The alteration is more important at high velocities. Motoneuronal excitability was estimated by using Hmax/Mmax ratio (Scaglioni et al 2003). This excitability seems to decrease in ageing. However, torques, under eccentric conditions, appear relatively preserved (Valour et al 2003, Pousson et al 2001). The twitch interpolation technique (Merton, 1954) allowed us to assess maximal voluntary activation capacities. The validity of this technique under isometric, concentric and eccentric conditions was evaluated and proved (Babault et al, 2001, 2002, 2003). Maximal voluntary activation capacities seem to be preserved in ageing. The effect of ageing on the mechanical and electromyographic characteristics of the motor units activated by the maximal Hoffmann reflex and by the direct muscle compound action potential was also assessed. Results suggest an on-going neuromuscular remodelling, resulting in an increased innervation ratio. The neural rearrangement may be viewed as a compensatory adaptation of the motor system to preserve the mechanical efficiency of the surviving motor units, despite the age-related impairment of the segmental reflex system (Scaglioni et al 2003). Muscular activities, Activation, Co-activation: The progressive decline in neuromuscular function and performance with aging can be estimated by the measure of the maximal voluntary contraction torque (MVC). However, this impairment of strength is muscle group dependent. Thus we made an original observation, whose functional implications in terms of stability in standing posture are crucial: at the level of the ankle joint, plantar-flexion (PF) MVC torques in elderly men were, on average, 40 % lower than in young adults, whereas there was no significant difference between the two age groups in dorsi-flexion (DF) MVC torques (Simoneau et al 2005). The decline observed in PF maximal performance would be partly explained by changes intervening at the peripheral level, i.e. at the muscle level. Hence, we investigated the effects of a 6-month strength training program of the plantar-flexors on muscular and neural factors of the major muscle groups (agonists and antagonists) around the ankle, in older participants. We have thus shown that older adults developed PF and DF MVC torques greater than those initially produced (Simoneau et al in press). A 6-month strength training program of the plantar-flexors in old age is very effective in recovering strength in PF, and thus reduced the imbalance in the DF-to-PF MVC torque ratio. However, this strength training does not seem to improve the reflex activity of the plantar-flexor muscles, which declines in the older adults, suggesting that this alteration could be linked to degenerative phenomenon (Scaglioni et al 2002). Contractility and elasticity: The main purpose of this part was to evaluate the plasticity of muscle elastic properties with aging and following a strength training program in older individuals. The first study (Ochala et al, 2004a) was designed to determine musculotendinous (in situ Quick-release) and musculoarticular stiffness (Sinusoidal perturbations) during plantar flexion in young and older people. The results showed a bigger musculotendinous stiffness in older individuals, what may be due to changes in the muscle tissue. Musculoarticular stiffness was similar between the age groups, suggesting an adaptive mechanism in articular structures to avoid the continuous integration of the musculoarticular stiffness by the central nervous system (simplifying most daily motor tasks). The second study (Ochala et al, 2004b) was devoted to evaluate differences between older women and men. The bigger musculotendinous and musculoarticular stiffness in women compared to men of the same age may be due to disparities in the muscle tissue and explain in part their greater frequency of falling. The third study (Ochala et al, 2005) was devoted to evaluate musculotendinous stiffness during plantar flexion in older individuals following a 6-month strength training program (48 sessions, twice a week, 3 sets of 10 concentric-repetitions at 75% of 3 RM). The smaller musculotendinous stiffness following training may be due to structural and neural adaptations, counterbalancing some effects of the neuromuscular aging.

This study was designed to investigate the effects of ageing on motor control and to identify the adjustments within the nervous system during fatiguing tasks in the human dorsiflexor muscles. The main results show that in advanced age, the loss of motor neurones usually observed is accompanied by an increase in the relative force of each motor unit and a decrease of their maximal discharge frequencies. Despite this profound remodelling of the motor system and reduced motor units discharge rate, the central neural command is still optimal for muscle activation and does not contribute to the observed reduction in muscle force and endurance during intermittent contractions. However, the slowing and decrease of the spinal and supraspinal reflex responses indicate that the balance of peripheral excitatory and inhibitory inputs into the motor neurones is modified with ageing. This observation further indicates that the sensory system is more affected than the motor system and consequently explains most of the degradation in skill performances during ageing. Findings of this study have practical applications in fitness and rehabilitation programmes. They emphasis the need of regular physical activities, involving not only strength exercises but also proprioceptive ones, in order to maintain or improve the functional capacity of the sensory-motor system during senescence. The results can also contribute to optimise ergonomic designs for elderly adults to compensate for impairments in muscular force and endurance.

Central (cardiopulmonary) and peripheral (at the skeletal muscle level) effects of ageing on muscle oxidative metabolism were evaluated in this study. A proteomic analysis of skeletal muscle samples was conducted by two-dimensional differential gel electrophoresis (2-DIGE), SDS analysis and subsequent identification of differently expressed proteins. The results show, in the elderly (E) vs. the young (Y): a downregulation of the degree of expression and phosphorylation of the regulatory isoforms of myosin light chains (MLC); myosin heavy chains (MHC) concentration characterised by greater MHC 1 and 2A; higher concentration of several oxidative enzymes, and lower concentrations of several anaerobic enzymes. The findings on MLC phosphorylation could explain, at least in part, the functional deterioration of ageing skeletal muscle. Ageing skeletal muscle, however, seems to show a shift towards a more oxidative phenotype, whose potential might be not fully expressed in normal conditions. E showed a significant decline (about 50%) of peak (the value determined at voluntary exhaustion) maximal aerobic power (VO2peak), as well as of the ventilatory threshold (VT) with respect to Y. The lower VO2peak was associated with lower HRpeak and with a lower maximal O2 extraction by skeletal muscle (O2 extraction was estimated at the level of the vastus lateralis by Near Infrared Spectroscopy [NIRS]). Arterial blood O2 saturation (SaO2) did not significantly decrease, both in E and Y. Thus, during cycloergometric exercise both central (but not pulmonary) and peripheral factors contributed to the lower VO2peak in E. Incremental exercises were also conducted by utilizing a protocol in which only relatively small (2-3 kg) muscle masses were involved, assuming that cardiopulmonary factors should not significantly contribute to the reduced aerobic performance. Knee extension exercises were conducted at 20%, 40% and 60% (3-min steps) of the force corresponding to 1 repetition maximum (1 RM). 1RM and the total lifted load were significantly (by about 40-50%) lower in E vs. Y. In both groups HRpeak was significantly lower that the HRpeak determined during cycloergometric exercise, confirming that the knee-extension exercise did not represent a significant burden for the cardiovascular system. Peak O2 extraction estimated by NIRS was higher in E vs. Y. Thus, after presumably allowing a better perfusion of the exercising muscles, E were capable to attain a higher O2 extraction than Y. During constant-load cycloergometric exercise below and above VT, O2 uptake (VO2) kinetics were significantly slower in E vs. Y. A slower VO2 kinetics negatively affects exercise tolerance, and is generally considered a variable of evaluation of oxidative metabolism in skeletal muscle. The slower VO2 kinetics in E was associated with slower O2 extraction kinetics. During exercise above VT E did not show, differently from Y, a slow component of VO2 kinetics, and presented less muscle fatigue (as determined by electromyography [EMG], evaluating the slopes of the Root Mean Square [RMS] vs. time profiles). The occurrence of a VO2 slow component is considered to be negative for exercise tolerance, and it is thought to derive from the recruitment of less efficient fast fibres. Thus, not only E showed VT at a higher percentage of their VO2peak, compared to Y, but were also capable to sustain constant-load exercise above VT without showing a slow component of VO2 and with less EMG signs of fatigue. The subjects underwent a 1-year training program (T), mainly characterised by strength training, with some aerobic exercises. T determined in E a significant increase in HRpeak, a tendency towards an increase in VO2peak, and an increase in maximal O2 extraction. Pulmonary VO2 kinetics were unaffected by training. As for the knee-extensor exercise, T in E determined a trend toward an increase in the total lifted load, an increased O2 extraction and less EMG signs of fatigue during the exhausting load. The relatively small effects of T on oxidative metabolism could be attributed to the low amount of aerobic work in the training sessions. In conclusion, there is a significant functional limitation of oxidative metabolism in ageing muscle, attributable to both central and peripheral factors. However, there could be a significant hidden oxidative potential in ageing muscle (see oxidative enzymes by the proteomic analysis, as well as the higher percentage of type 1 and 2A fibres), as also suggested by some functional variables (e.g. higher VT, no slow component, less fatigue during constant-load exercise >VT, higher O2 extraction during knee-extension). Some effects of training were observed (e.g. slightly higher VO2peak, HRpeak, peak O2 extraction during cycloergometric exercise; less fatigue during knee-extension exercise), even if the training protocol was not specific for aerobic metabolism.

Data were collected on healthy young and older people. The third group studied were an age-matched group of older people who fell for medically unexplained reasons. Maximal voluntary strength was tested in the quadriceps, hamstrings, dorsi- and plantar- flexors at a range of a) knee angles for isometric contractions and also b) angular velocities for concentric and eccentric contractions. During isometric contractions the older subjects were significantly weaker than the younger group in all cases. The length:tension relationship was similar in these two groups, indicating that the muscle/tendon complex remains essentially the same length. The fallers were generally weaker than the age-matched non-fallers and this was particularly obvious in the knee muscles at shorter lengths. During dynamic contractions the older group had better preserved eccentric force generation than either isometric or concentric and in general, dynamic force generation was better preserved at higher angular velocities. The older fallers generally produced similar dynamic forces to the older non-fallers, except for the plantar-flexors where the fallers were weaker. Voluntary activation in the quadriceps was similar in the two age groups and also in the elderly fallers. Co-contraction of antagonist muscles during isometric and dynamic maximal voluntary contractions was similar in the two age groups. The fallers had higher levels of co-activation in the plantar flexors during eccentric dorsiflexion, otherwise there was no difference between them and the non-fallers. Intrinsic force of the quadriceps as measured by ultrasonography of the anatomical cross sectional area was similar in both age groups. The fallers had a lower intrinsic force than the non fallers in all contraction types, but this did not reach statistical significance. Leg extension power output was significantly less in the older subjects while the ratio of isometric strength: power was similar in the two age groups. It was similar in the two older groups. Asymmetry of strength tended to be slightly greater in the older subjects, but there were generally no significant differences between older and younger people. It was similar in the fallers and non-fallers. Asymmetry of power was similar in all three groups. Greater asymmetry of isometric strength was found at some, but not all, joint angles in the hamstrings and dorsiflexors of the fallers and during slow eccentric contractions. Correlations between strength, power and the number of falls. Reduced strength and power were strongly associated with falling. Steadiness was measured during isometric, ansiometric & functional activities (stepping up and down, standing up and sitting down. During isometric and eccentric ansiometric contractions the older subjects tended to be less steady than the young and the fallers were less steady than the non fallers. During functional activities the older subjects were less steady, but there were no differences between fallers and non-fallers. In the fallers steadiness was particularly reduced during eccentric contractions. Training. Elderly fallers and non-fallers responded similarly to a one year training programme. This resulted in significant increases in strength of the quadriceps and hamstrings muscles (but not the dorsi-or plantar- flexors), power output and power symmetry. It had no effect on steadiness during isometric, ansiometric or functional activities or strength symmetry. The inclusion of a 10 minute period of Tai Chi in the supervised programme did not affect the results in any way. Conclusions: These results suggest that of the muscle measurements made, reduced strength and power output are the most important factors associated with falling in older people, along with reduced steadiness. Most of the measurements of muscle function revealed clear differences between young and older people and, although age matched, the fallers appeared to show greater changes than their chronological age would suggest. Increased asymmetry of strength or power did not seem to identify fallers as has previously been suggested. Fallers demonstrated a training response that was the same as that seen in people of a similar age who did not fall and therefore training should be effective in reducing the risk of falling. The inclusion of a short period of Tai Chi in the training sessions was not associated with any increased physiological benefit, although it may be effective in improving confidence and habitual levels of physical activity.

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