Protein Intake and Step Reduction in Older Adults
Condition: Aging; Muscle Loss
Study type: Interventional

Summary: 
      Sarcopenia, the loss in muscle mass with age, is associated with several negative health
      outcomes including cancer, stroke, cardiovascular disease and diabetes. This loss of muscle
      mass remains relatively steady following 50 years of age however it can be accelerated with
      periods of disuse associated with hospitalization, fracture or surgery of the hip or simply
      influenza. Also associated with periods of disuse, is a lack of energy intake as
      hospitalizations often result in undernourishment. The consumption of protein has been shown
      to stimulate muscle growth and therefore the investigators are wondering whether it is able
      to offset the loss of muscle mass associated with disuse. Therefore, the purpose of the study
      is to examine the effects of protein consumption combined with mild caloric restriction on
      changes in muscle mass and function during a period of disuse as well as during a period of
      recovery .
    

Detailed description: 
      The age-related decline in skeletal muscle mass, termed sarcopenia, is associated with a host
      of metabolic disease states including, but not limited to, cancer, stroke, microvascular
      disease, type 2 diabetes, Parkinson's and Alzheimer's. Moreover, declines in skeletal muscle
      mass also are accompanied by an even more precipitous reduction in skeletal muscle strength,
      known as dynapenia, which is a predisposition for disability and falls.

      Sarcopenia begins in the 5th decade of life and proceeds, at least based on population-
      derived estimates, at a ~0.8% loss annually, with strength losses being greater and more
      variable at 2-5% year past the age of 50. However, these rates of muscle and strength loss
      are not linear. Rather, the steady decline in muscle mass loss is punctuated by short-term
      periods of muscle disuse, which accelerate strength and muscle loss and from which older, as
      compared to younger, persons have a difficult time recovering. These acute periods of muscle
      disuse have been shown to result in a transient accelerated decline in strength and skeletal
      muscle mass effectively accelerating sarcopenia. Such episodes of muscle inactivity manifest
      from a variety of circumstances such as hospitalization requiring short-term bed rest,
      immobilization of limbs due to fracture or surgery, and periods of inactive convalescence
      from illnesses. For example, influenza is the second most common cause of short-term
      hospitalization in persons 65y with an average hospital stay of 3-4d in duration during which
      substantial muscle disuse occurs. In addition, many surgeries in older persons (e.g.,
      cholecystectomy), are followed by a hospital stay averaging 3d with a 6-9d period of
      recovery, or an average of ~10 d of convalescence and minimal activity before a return to
      normal activity. Given that physical strength is a predictor of all-cause mortality,
      strategies that prevent the decline in, or enhance the recovery of, skeletal muscle strength
      and functional mass following periods of inactivity in the elderly are critical.

      Data from our lab and others have shown that reduced ambulation (i.e., reduced daily steps),
      a model of a remarkably common but seemingly benign state of muscle disuse, leads to a
      significant loss of skeletal muscle in both young and older individuals. The investigators
      propose that a period of disuse induced through step reduction provides an excellent model by
      which to study disuse-induced dynapenia and atrophy. In older persons, 2wk of reduced
      activity has been shown to decrease leg lean mass by 3.9% and increase in trunk adipose
      tissue by 7.3%. Interestingly, others have demonstrated that older individuals lose the same
      amount of muscle with only 10d of bed rest as compared to that lost with 28d of bed rest in
      young persons. During the same 10d period there is shocking loss of lower extremity strength,
      power, and aerobic capacity, and a reduction in physical activity. These data demonstrate
      just how susceptible older persons are to even short-term periods of disuse. Different
      results were observed by Suetta et al, who reported, in response to 14d of leg casting, an
      8.9% and a 5.2% decline in quadriceps femoris muscle volume in young (n=9) and old men (n=9),
      respectively. What needs to be appreciated, however, is that the older subjects had an 11%
      lower muscle volume prior to immobilization (i.e., sarcopenia) so the loss in muscle mass may
      have even more dire consequences for the older subjects . More importantly, older men showed
      recovery of only 63% of their muscle mass and ~78% of their strength with 4wk of intensive
      resistance training (which is not standard rehabilitation), versus a complete recovery in
      young men. The investigators also have preliminary data that shows 2wk of step reduction
      results in a significant decline in skeletal muscle strength in older men.

      One potential strategy to alleviate disuse-induced muscle atrophy that occurs during physical
      inactivity would be to increase dietary protein intake. Indeed, some studies show that high
      doses of amino acid ingestion slow the rate of disuse atrophy during bed rest. However, more
      recently, Dirks et al reported that increasing protein intake from 1.1g/kg/d to 1.6g/kg/d,
      using a twice daily supplement of 20g of protein, had no impact on skeletal muscle disuse
      atrophy during 5d of immobilization by means of a full leg cast. The lack of agreement
      between studies has been highlighted as being related to differences in the protein intake
      between the control groups. Indeed, in the studies that did show attenuation in muscle mass
      loss during bed rest, the control groups were consuming protein at a rate no higher than
      0.8g/kg/d whereas in the latter study participants in the control group consumed 1.1g/kg/d
      and it is also hypothesized that the protein dose used by Dirks et al was suboptimal since
      our work shows that higher protein doses of whey protein are required by older men to
      optimally stimulate protein synthesis. The investigators have recently showed, using a
      retrospective pooled analysis of muscle protein synthetic rates, that older men had a higher
      per meal protein requirement to optimally stimulate protein synthesis. Importantly, this work
      also showed that with a sufficiently high dose of whey protein (~30g) older men had rates of
      muscle protein synthesis not different from those in young men. Thus, while it is appreciated
      that twice daily consumption of a 30g supplement would substantially elevate protein intake,
      this intake would still be well within the Acceptable Macronutrient Distribution Ranges and
      appropriate for older individuals who are inactive and hypoenergetic. Moreover, the study by
      Dirks et al was conducted in a 'free-living' setting insofar as diet was concerned. The
      investigators propose that during periods of hospitalization and convalescence, elderly
      individuals often experience an energy deficit and are undernourished, specifically with
      respect to protein intake . Indeed, a study of 102 hospital patients demonstrated that 21%
      were consuming only 50% of their daily energy requirements and this under-nutrition was
      associated with a higher incidence of in-hospital and 90d post-discharge mortality. Similar
      findings have been corroborated by other reports that also show that under-nutrition is
      largely driven by inadequate protein intake. This latter point is highly relevant to our
      application as during times of energy deficit up to 25% of body mass loss can be accounted
      for by losses of lean body mass. Taken together, these data show that periods of muscle
      disuse are often accompanied by periods of energy deficit in the elderly. This situation also
      is highly likely to be the case during, for example, wintertime in Northern regions of Canada
      and the US when older adults, particularly those who live in single occupancy households, may
      be homebound and thus drastically reduce their activity levels and are less likely to walk to
      retail outlets.

      The mechanistic basis of the age-related loss of skeletal muscle mass and function Losses of
      skeletal muscle mass are underpinned by an imbalance between rates of muscle protein
      synthesis (MPS) and muscle protein breakdown (MPB). In healthy humans it is known that the
      change in the rate of MPS in response to contractile activity and protein feeding is the
      primary locus of control for human muscle mass. In this regard, the investigators have
      recently shown that postprandial MPS in response to protein ingestion is reduced by
      approximately ~20% following 14d of step reduction in older men and women, and this reduction
      in postprandial MPS - coined 'anabolic resistance' - was associated with a ~3.9% loss in fat
      free leg mass over the 14d period. Thus, it is proposed that reduced anabolic sensitivity to
      protein ingestion is primarily responsible for skeletal muscle disuse atrophy in humans.
      Relevant to the setting of hospitalization, short-term energy deficits also reduce
      postprandial MPS in young and the investigators have preliminary data to show that 14d of a
      controlled hypoenergetic diet also reduces MPS by approximately ~9% in middle-aged men and
      women. It therefore appears that both reduced ambulation and a state of energy restriction
      independently (and possibly synergistically) have a deleterious impact on MPS in response to
      protein ingestion that may explain the rapid and punctuated losses of skeletal muscle mass
      and strength that can occur with advancing age. Our laboratory has published data to show
      that increased consumption of dairy foods and protein during diet and exercise-induced weight
      loss results in lean mass gain whilst concomitantly promoting fat mass loss in overweight and
      premenopausal women. Yet, how increasing dietary dairy-based protein intake during, and in
      recovery from, a period of combined reduced ambulation and hypoenergetic diet influences
      muscle anabolism in older men and women remains unknown. Another discerning feature of
      protein metabolism with aging is that although there are no apparent differences in protein
      turnover between young healthy males and females, older females demonstrate elevated rates of
      resting MPS versus older males (>70y) but are less sensitive to the anabolic effects of
      protein feeding and exercise. The implication of this phenomenon is that elderly women may be
      at even greater risk from disuse atrophy during periods of physical inactivity and
      sub-optimal protein intake compared with men.

      Many of the aforementioned studies that assessed acute changes in rates of MPS in response to
      protein intake did so by infusing a labeled amino acid tracer and calculating the
      incorporation of that tracer into skeletal muscle over a period of hours (for extended
      discussion see). While this approach provides important information, especially when coupled
      with quantitative measures of changes in muscle mass such a MRI, the assessment of
      tracer-infusion measured MPS is limited to ~5-6h. More recent developments of analytical
      techniques have enabled the use of a deuterated water methodology that enables assessment of
      MPS with much longer periods of incorporation i.e., days-to-weeks. Indeed, this method has
      been recently validated and its use is now becoming the interest of many researchers.
      However, only a few laboratories have demonstrated the ability to competently perform this
      measurement. In fact, the investigators have recently conducted two studies using this
      methodology, and the MPS values that have been obtained are entirely consistent with
      published reports. It is proposed that the use of the deuterated water methodology, which
      allows measurement of MPS in a free-living situation and incorporates all dietary and
      activity measures, would be a substantial advance in determining mechanisms underpinning
      disuse-mediated muscle protein loss. Thus, the investigators aim to build on these findings
      by using the deuterated water methodology to study how increasing dietary protein intake
      during, and in recovery from, a period of combined reduced ambulation and energy deficit,
      influences long-term rates of MPS in older men and women.

      The molecular mechanisms that underpin MPS in response to stimulation are complex,
      multifactorial and remain largely unknown. However, what is known is that proteins contained
      within the Akt-mTORC1-p70S6K1 signalling axis appear key. In a study conducted by the
      investigators involving reduced steps, it demonstrated a reduction in Akt phosphorylation as
      well as a ~12% reduction in insulin sensitivity. Thus, the investigators propose to examine
      how the content of proteins contained within the Akt-mTORC1-p70S6K1 signalling axis change
      during our intervention. The investigators will also will examine changes in the DNA-protein
      ratio (an indicator of cell size) as well as mRNA expression of myogenin, MAFBx and MuRF1,
      some of which have been shown to change in response to a period of disuse atrophy, using
      real-time PCR. Thus, our molecular analysis coupled with the use of the deuterated water
      methodology, and a real-world model of disuse atrophy and negative energy balance, provides a
      mechanism-based clinical approach to study the impact of increased protein intake on
      age-related myopenia and dynapenia.

      The investigators have previously shown that 14d of reduced steps induces a reduction in
      postprandial MPS by approximately ~20% following in older men and women, and this reduction
      in postprandial MPS was associated with a ~3.9% loss in fat free leg mass. It has been
      demonstrated that increased consumption of dairy foods and protein during diet and
      exercise-induced weight loss results in lean mass gain whilst concomitantly promoting fat
      mass loss in overweight and premenopausal women. Building on these findings, the
      investigators have recently generated pilot data to show that 14d of step reduction results
      in a significant decrease in muscle strength. In addition, it showed an ~18% reduction in
      postprandial MPS in response to 3 separate 25g servings of whey protein over an 11 h periods
      following 14d of mild energy restriction (-300 kcal) in healthy older males (~65y). Moreover,
      the investigators have preliminary data to show that 14 d of a hypoenergetic diet (-750
      kcal/d) induces a significant decrease of 9% in postprandial MPS in obese, overweight men and
      women aged 35-65y . Finally, the investigators have just successfully completed a complex
      human trial in older men (65-75y) who completed a single bout of either resistance exercise;
      high-intensity interval exercise or traditional low-intensity aerobic exercise aimed that
      utilized the D2O tracer methodology to directly assess MPS over a 24h and 48h period. These
      MPS values are entirely consistent with previously published data.
    

Intervention name(s): Whey; Collagen
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Supplement provided twice daily in 30g doses; Supplement provided twice daily in 30g doses
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel group design (with repeated measurements within each group)
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Protein ingestion; Muscle protein synthesis