MUSCLE GROWTH

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SEPTEMBER 3, 2016

Anabolic Resistance: Why It Is Harder To Add Muscle Mass As We Age And How To Fight It
(Research-Based Recommendations From 60+ Studies And Reviews)
Thanks to Greg Nuckols of Strengtheory for giving me feedback when writing this article.
This article is presented to you as a source of information. I make no judgements on whether a treatment is right or wrong I only
present you the options. This is not medical advice. Please consult your doctor before you consider any drastic measures.

SUMMARY
We lose muscle mass and strength as we age. This is known as sarcopenia.
Muscle loss could begin in our 30s. Genetics and lifestyle play a major
factor and there is a lot of inherited individual variability (not everyone is
the same!!!).
There are several reasons why we become weaker: Our nervous system
becomes more inecient, our muscle quality decreases, our anabolic
hormone secretion decreases, our bodies develop chronic inammation
and anabolic resistance.
How to prevent age-related muscle loss: eat more protein at least 1.2g/kg
BW up to 2g+/kg (counter-indication: careful if you have damaged kidneys),
strength training with high intensities and volumes, active lifestyle outside
the gym, supplement various nutrients like vitamin E, D, and omega-3s (if
you are decient).
There are also riskier solutions, but for those you have to see your doctor.

INTRODUCTION
Aging is a complicated phenomena, but I think most of us have seen what can happen to the human body as it ages. Naturally, we
start to wonder what will happen to our own bodies. Ive read dierent experiences and opinions online, where some people
suggest that aging basically kills the bodys hypertrophic potential, while others say age has no eect on gains until we get well into
our 70s. Today, Ill examine dierent aspects of aging and how it aects our body composition and athletic potential.
Before we start, Ive placed footnotes in the sentences. These footnotes refer to specic quotes from research articles. At the end of
the paragraph you can expand a box that shows these quotes.
If you nd this article dicult to read or understand, just scroll down to or ctrl+f this section: How to treat and prevent age-related

muscle loss (practical applications for your life).

SARCOPENIA
The body slowly loses its ability to build muscle mass and increase strength as we age (Horstman et al., 2012; Timmons &
Gallagher, 2016; Brook et al., 2016; McLeod et al., 2016; Mitchell et al., 2016; Jang, 2016; Shad et al., 2016). This is called sarcopenia,

but it has no single cause. The following is an graph from McLeod et al., 2016 and it shows muscle CSA and how it relates to age:

We see a clear downwards trend. In addition to this, Mitchell et al. (2012) suggest that we lose ~5% muscle mass per decade,
starting somewhere in our late twenties. Tan et al. (2012) report that skeletal muscle mass drops from ~45% total body weight in
our late twenties to ~27% at 70 years old. This result is pretty similar to Mitchells. Other research groups list more dramatic
numbers. They say we could lose 0.5-2% muscle mass per year, starting somewhere in our thirties/early forties 1 2 3. One study
actually reports that men observed from 15-83 started atrophying after the age of 25 (McLeod et al., 2016)!!! Looking at these
studies together, I think its safe to assume that people could lose muscle mass in their thirties. However, there are notable
individual exceptions (Clark and Manini, 2012), as we will see later when we discuss genetic predispositions.
Click to expand quotes 1-3
In addition to muscle atrophy, we lose strength as we age. Below is an illustration fromDelmonico et al., 2009. On the left graph
you can see that people that lost muscle mass with aging also got much weaker. On the right side, the subjects gained muscle
mass, but still lost strength.

So researchers now believe that there are other mechanisms that impact strength beyond muscle mass. These mechanisms
become downregulated with age so that even if you maintain or increase muscle mass, youre bound to get weaker (Mitchell et al.,

2012; Clark and Manini, 2012; Wagatsuma and Sakuma, 2014). Several research teams estimate that we lose ~2-4% strength per
year as we get older 4 5 6. Note: this number may not directly apply to you if youre actively doing strength training. We will discuss

this in more detail further down.

Click to expand quotes 4-6
Researchers now think sarcopenia comes from a combination of many factors, like: muscle disuse, neuron atrophy, CNS
ineciency, declining anabolic hormones, low protein intakes, anabolic resistance, micronutrient deciency, genetic predisposition,
diseases, mitochondrial ineciency, decreasing muscle quality, and chronic inammation. Im going to discuss these mechanisms
in the following section.

WHAT CAUSES MUSCLE LOSS?

Inactivity, atrophy, and muscle quality
As we get older, were much more likely to be sedentary. Many researchers wonder whether we become sedentary before we lose
muscle mass, or whether we become sedentary because we lose muscle mass 7 (Peterson and Gordon, 2011). Its hard to say for
sure, but some researchers think muscle mass decreases because muscles lose their quality. By quality I mean ability to produce
force. For example, muscles generate less force per unit of CSA with age (Mitchell et al., 2012; McGregor et al., 2014). More fat is
deposited into muscle tissue possibly making muscles more inecient (McGregor et al., 2014; Delmonico et al., 2009; Wagatsuma
and Sakuma, 2014). Looking at molecular mechanisms, some studies suggest aging muscles develop problems with muscular
contractions because of an impaired calcium release mechanism 8.
Click to expand quotes 7-8

Anabolic resistance
Similarly to muscle quality, anabolic resistance is also a local mechanism. When we look at how the body responds to exercise, we
see that it adapts by making our muscles more resistant to change. This has been studied in young lifters and its called anabolic
blunting (Coey et al., 2005; Mangine et al., 2015; Gonzalez, 2015; Gonzalez et al., 2015a; Noguiera et al., 2015). In short, this
blunting means that muscle protein synthesis and mTOR become harder to activate the more trained you get. In theory, this would
partially explain why we experience diminishing returns as we grow bigger and stronger. So how does this link to aging? Theres
now a debate whether anabolic resistance could happen to older people as well, even if theyre untrained. Some studies nd that
older lifters show anabolic resistance to strength training and nutrition (Kumar et al., 2009; Vingren et al., 2010; Horstman et al.,
2012; Markofski et al., 2015; Moore et al., 2015; Wall et al., 2015;Moro et al., 2016; Timmons & Gallagher, 2016; Loenneke et al.,
2016; McLeod et al., 2016; Mitchell et al., 2016; Shad et al., 2016). The theory is that the body slowly downregulates MPS and mTOR
in a response to aging.
On the other hand, a new systematic review has just been published and it nds only partial support for the claim that MPS
signalling becomes weaker with age (Shad et al., 2016). Shad et al. think a big reason theres so much contradiction in the MPS
literature is because of methodological dierences between studies. A big limitation to Shads review is that the majority of the
studies they included only measured mixed muscle protein synthesis. This type of MPS does not predict hypertrophy. We need to
look at myobrillar protein synthesis (myoMPS) (Moore et al., 2009) if we want a shot at predicting gains (and in many cases,
myoMPS does not predict gains either) (ASM). Heres an illustration of the dierences between mixed MPS and myoMPS post-

exercise: (illustration from Damas et al., 2015).

Ideally, Shad et al. would discard studies that measured mixed MPS and only analyze myoMPS. And since Shad isnt here right now
Ill do it myself; out of the 24 studies included in Shads review, 5 dealt with myoMPS. Three studies found a clear dierence
between young and old in terms of myoMPS responses (Babraj et al., 2005; Cuthbertson et al., 2005; Kumar et al. 2012), one study
found dierences at some time-points (Kumar et al. 2009), while one study found no dierence (Atherton et al., 2016).
Heres an illustration of the dierences, as per Kumar et al., 2009:

When we eliminate the mixed MPS studies, we see greater support for the anabolic resistance theory. There are also other studies
outside of Shad et als. review that support this (Welle et al., 1993; Welle et al., 1995; Yang et al., 2012). Several of these studies
show that mixed MPS is actually quite similar between old and young, but myoMPS is blunted in the old 9 10.
Click to expand quotes 9-10
You might come across studies entitled Aging does not impair the anabolic response to a protein-rich meal (Symons et al., 2007),
and they might seem convincing at rst sight, but once you read conclusions like Mixed-muscle FSR increased by approximately

51% in both [old and young] you get disappointed at the researchers for not controlling for myobrillar MPS.
From the information Ive presented here, I think its likely that MPS-related anabolic resistance exists. Beyond the studies that Ive
explicitly linked in this section, many of the studies and reviews I discuss in this article agree that MPS-related anabolic resistance is
real. However, I will add the limitation that I have not systematically reviewed the literature, so it is possible that there are studies
out there that contradict this hypothesis. In that sense, my conclusions are tentative, pending further evidence (as is everything in
science). Furthermore, do note that MPS correlates with gains only in some situations. In most situations researchers have looked
at to date, it does not (ASM).

Declining anabolic hormones

Beyond mechanisms that aect the muscle tissue locally, the body experiences systemic changes with age. Most notably, systemic
anabolic hormones like IGF-1, GH, and testosterone are reduced (Ryall et al., 2008; Vingren et al., 2010; Horstman et al., 2012; Tan
et al., 2012; Fan et al., 2016; Budui et al., 2015). These reductions probably leads to muscle loss (Horstman et al., 2012; Vitale et al.,
2016). Testosterone drops by about 1-3% per year, beginning sometime during your thirties 11 12, GH and IGF-1 secretion declines
by 14% per decade after the age of 30 13, and tissues become more insulin insensitive(Vitale et al., 2016)
Heres a relevant illustration by Ryall et al., 2008:

Click to expand quotes 11-13

Inammation
As we age, our bodies develop constant low-level inammation (Jensen, 2008; Peterson and Gordon, 2011; Fan et al., 2016). Chronic
inammation likely aects muscle mass and strength negatively 14 15 16 17 18 19 20. There are several causes (Fan et al., 2016):

It gets even worse if you have diabetes, because this condition is characterized by inammation (Park et al., 2009; Kalyani et al.,
2014; Khor et al., 2014; Koster and Schaap, 2015; Jang, 2016; Vitale et al., 2016).
Click to expand quotes 14-20

Nervous system ineciency and neural activation

The nervous system degenerates with age and it goes through multiple changes. Notably, the PNS loses muscle neurons (Frontera
et al., 2011; Clark and Manini, 2012; Tintignac et al., 2015). These neurons are nerve cells that go from the spine to muscles and
they control muscle contraction. Many authors now think this loss of neurons partially explain why muscles atrophy and we
become weaker as we age(Kwan, 2013; McLeod et al., 2016) 21 22 23. However, others say that this might be the case, but we
should wait for stronger evidence before we conclude anything for sure 24 (Manini et al., 2013). On the other hand, Maninis review
is from 2013, and newer reviews think there is enough evidence to make conclusions (Sakuma et al., 2015). Beyond the physical
decrease in motor neurons, the nervous system generally becomes more inecient at sending messages. Manini et al. (2013)
describe this as neural noise (i.e. static noise) which leads to breakdown in communication between brain and muscle. Aging
people could therefore have problems with voluntary neural activation and lowered maximal contraction 25.
From Clark and Manini, 2012: (Dynapenia = Dynapenia is the age-associated loss of muscle strength that is not caused by
neurologic or muscular diseases)

Click to expand quotes 21-25

Genetics
Genetics is a huge and complicated subject so I will try to simplify as much as possible here. Researchers think people have
dierent phenotypes. A phenotype is basically a collection of observable traits (physical features, mental abilities, etc.). Phenotypes
are created from an organisms genes and their interaction with the environment. We now think that some phenotypes are at
greater risk for sarcopenia because of heritability. Its estimated that muscle strength is 30-85% genetically inherited, while muscle
mass is 45-90% inherited (Roth, 2012; Pereira et al., 2013), but the estimations vary depending on which review and study we look
at (Tan et al., 2012).
In addition to heritability, we have individual variation. Some individuals could lose a lot of muscle mass as they age, while others
do not (Clark and Manini, 2012; Tan et al., 2012). This has been studied recently, and some older people that do strength training
actually lose muscle mass. These people are referred to as non-responders, and it also happens in young subjects. You can see the
non-responders at the bottom of this graph by Churchward-Venne et al., 2015:

There are some issues with measuring fat mass, LBM, water, etc. using DXA/BIA and similar methods. However, I wont go into that
topic in this review.
We can also look at individual genes and analyse their relationship to muscle loss. The ACE, ACTN3, MSTN (myostatin), CNTF and
VDR (vitamin D) genes are promising 26 (Khor et al., 2014). Some authors claim each of these genes can contribute 1-3% when it
comes to skeletal muscle variation 27. Its possible that genes can also have synergistic eects. For example some genes could have
a much stronger eect when combined 27. In that sense, no gene exists in isolation.
Click to expand quotes 26-27

Low protein intakes

Its highly likely that sarcopenia is aected by low protein intakes (Shad et al., 2016). In fact, we need more protein the older we get
(Moore et al., 2015; Philips, 2015; Shad et al., 2016; Mitchell et al., 2016; McLeod et al., 2016; Loenneke et al., 2016; Courtney-Martin
et al., 2016; Baum et al., 2016). Adults that eat a lot of protein maintain~40 % more muscle mass compared to those that eat very
little protein 28.
Click to expand quote 28

Micronutrient deciency
Micronutrients are vitamins and minerals. It generally goes without saying that its really important to get enough micros regardless
of age. There are some micros that are particularly interesting; vitamin D. In general, low vitamin D levels could lead to muscle
atrophy and reduced strength (Robinson et al., 2012; Roth, 2012; Wagatsuma and Sakuma, 2014; Khor et al., 2014; Wakabayashi
and Sakuma, 2014; Budui et al., 2015). Nevertheless, theres a big BUT here: pretty much every review of the vitamin D literature
agrees that results are inconclusive, so we cant say for sure how much vitamin D deciency matters when it comes to strength and
muscle mass.

Other causes (satellite cells, mitochondria, ROS, ber types)

I dont have the time nor inclination to look at every single potential cause for sarcopenia in this article, but I will link you an
illustration from (Miljkovic et al., 2015) that summarizes some potential causes:

HOW TO TREAT AND PREVENT AGE-RELATED MUSCLE LOSS (PRACTICAL APPLICATIONS FOR
YOUR LIFE)
The following section is presented to you for information purposes only. It is not medical advice. Please consult your doctor before

you consider any drastic measures.

Protein recommendations
The single most important recommendation from pretty much every review Ive read on the issue is to increase your protein intake
(Shad et al., 2016; Mitchell et al., 2016; McLeod et al., 2016). These are the recommendations from recent reviews: eat 30 to 50
grams protein per meal(Philips, 2015; Loenneke et al., 2016; Shad et al., 2016) and try to get at least 1.2g protein per kg
bodyweight throughout the day (Shad et al., 2016; McLeod et al., 2016; Courtney-Martin et al., 2016). However, a recent review by
Baum et al., 2016 criticizes these recommendations because they do not account for factors like muscle protein breakdown. Baum
et al., think these recommendations are still too mild, and that older adults need to up protein intake to ~35% of their total caloric
intake. So lets do some math:
Lets say you have a 60 year old man who weights 70 kg. His TDEE is 2200 per day. According to the mild recommendations, he
needs at least 70kg*1.2g = 84grams of protein per day. 84g*4 = 336 kcal. 336kcal/2200kcal = 15% protein of daily caloric intake.

Now if we use Baums model, the man would have to double his protein consumption to 168g. However, Baum et al. admit that
practical limitations may make this level of dietary protein intake dicult (Baum et al., 2016).
Recommendation: Its hard to say exactly what the recommendation should be, but I think its fair to suggest 1.2 protein per kg bw
is the lowest acceptable limit, with protein intakes up to and (possibly) exceeding 2g per kg bw, especially if youre doing resistance
training. Please consult your doctor before you drastically increase protein intake (in case you have kidney issues that could be

exasperated with increased protein load) (Examine.com)

Some studies show that protein supplementation could have an anti-inammatory eect in addition to being anabolic (Draganidis
et al., 2016).

Resistance training
Strength training, along with high protein intakes, prevents muscle atrophy and it becomes more important with age (Hurley and
Roth, 2000; Roth et al., 2000; Martel et al., 2006; Jensen, 2008; Peterson et al., 2010; Peterson and Gordon, 2011; Basharat et al.,
2012; Mitchell et al., 2012; Sakuma et al., 2014; Wakabayashi and Sakuma, 2014; Philips, 2015; Sakuma et al., 2015). One metaanalysis suggests higher intensity improves strength to a greater extent in older adults (Peterson et al., 2010). A follow-up review by
the same authors reported that higher volumes are better for hypertrophy in aging adults (Peterson and Gordon, 2011). This is
now armed by a recent meta-analysis by Schoenfeld et al. (2016). Here are Schoenfelds recommendations:

Based on our ndings, it would appear that performance of at least 10 weekly sets per muscle group is necessary to maximise
increases in muscle mass. Although there is certainly a threshold for volume beyond which hypertrophic adaptations plateau and
perhaps even regress due to overtraining () the optimal RT dose will ultimately vary between individuals, and these dierences
may have a genetic component () practitioners should carefully monitor client progression and adjust training dosages based on
the individual s response. (Schoenfeld et al., 2016)
From a molecular perspective, doubling volume from 3 to 6 sets enhances MPS in older men but not young men (Kumar et al.,
2012). Like Ive said before, its dicult to predict gains with MPS, but I still wonder why MPS continues to increase in older men
while it stops early in young men.

Hormone therapy
I am not making any recommendations in this section. It is provided for informational purposes only.
Low testosterone levels might lead to loss of muscle mass, declining strength, lowered bone mass, and more central body fat
(Horstman et al., 2012). Some authors suggest testosterone replacement therapy as a solution (Khor et al., 2014; Vitale et al., 2016).
However, they emphasize that it has some health risk, especially if you take testosterone doses that are supra-physiological
(beyond natural ranges) (Horstman et al., 2012; Khor et al., 2014; Budui et al., 2015; Vitale et al., 2016).

Lifestyle
One study found that making young men walk less gave them temporary anabolic resistance (i.e. blunted MPS response to protein)
(Moro et al., 2016). Theres reason to believe that an active lifestyle (outside of the gym) is generally better for maintaining muscle
mass and physical function (Malafarina et al., 2013; Atkins et al., 2014)

Preventing chronic inammation through supplementation

As mentioned, chronic inammation could cause atrophy (Horstman et al., 2012). There are some ways to ght this inammation:

Vitamin E (Khor et al., 2014; Rondanelli et al., 2015)

Omega-3s (Smith, 2016)
Protein supplementation (Draganidis et al., 2016).
Avoiding and/or treating diabetes
Vitamin D (might be anabolic) (Robinson et al., 2012; Wagatsuma and Sakuma, 2014; Morley, 2016)
However, I should note that there are a lot of studies that show supplementing large doses of antioxidants (vitamin A, C, E) can
actually prevent training adaptations in young subjects. So be careful about micronutrient supplementation if youre not decient. I
will publish an article on this in the future.

CONCLUSION
We lose muscle mass and become weaker as we age. This is due to various neurological, muscular, hormonal, and molecular
mechanisms that change as we age. Our nervous system becomes more inecient, our muscle quality decreases, our anabolic
hormone secretion decreases, our bodies develop chronic inammation, and we develop anabolic resistance. Theres still a lot of
discussion as to which of these mechanisms is the primary cause of muscle loss. Regardless of which one is the primary cause,
most authors agree that we start to lose muscle mass during our 30s and that there are many small causes rather than one big
one. In any event, we can prevent muscle loss by ingesting more protein (at least 1.2g/kg bw), by strength training with high
intensities and solid volumes, by having an active lifestyle outside the gym, and by supplementing various nutrients like vitamin E,
D, and omega-3s (if you are decient). There are also riskier solutions, but for those you have to see your doctor because I cannot
give you medical advice.
Our genetics also inuence how susceptible we are to muscle loss as we age. Some people are simply more likely to win the genetic
lottery, even though I know saying this has a strong undertone of eugenics. But I promise that insurance companies wont charge
you more for your bad genes that predispose you to disease and sarcopenia Yet
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