The UCL "Epidemic" Part 2: Early Tissue Senescence May be a Determinant

Alek Manoah underwent elbow reconstruction during the 2024 MLB season

Absolute’s Thesis

We finished Part 1 of this series focusing on our belief that a multitude of factors have intertwined to become determinants of a very large arm injury problem within the sport of baseball.

It is our belief at Absolute that a portion of this issue can be attributed to early biological tissue breakdown that stays unchecked and unmitigated and leads to system dysfunction later on, mostly as the demands of the system (workload, output) increase.

What we have noticed is that those pitchers that suffer catastrophic arm injuries are typically high performers that break down at a relatively early chronological age, showing that there is something significant that occurs over time, whereby the athlete seems to sustain this high level of performance until a very specific time earlier on in their careers where injury results and performance is compromised.

We would like to propose a theory as to why this may be.

The Case of Two Different Strains of Mice

To begin our discussion on early benefit, with late consequences we must discuss the fate of mice. Rest assured it is relevant to our theory. Bret Weinstein, an evolutionary biologist made a Nobel worthy scientific discovery concerning the breeding patterns of mice used in the lab to study cancer and tissue based diseases. In short, it turns out that mice that are bred in captivity are different genetically than mice that are left in the wild. Weinstein found that those that were bred in captivity were far more likely to sustain tissue based tumours, which made them great lab specimens but they were not representative of the mouse population as a whole as their environment was very controlled and very specific. This is similar to precocious young athletes who are often embedded in a positive feedback loop of athletic success leading to more of the same athletic activity essentially becoming lab mice specific to the sport. In the case of the mice, genetically different does not impact the nucleotides within the DNA sequence but specifically the telomeres, which are protein based “caps” on the ends of the DNA strand that allow for protection during controlled growth and regeneration of the internal environment. Those mice that were bred in captivity to become lab mice had longer telomeres, which is directly opposed to those mice in the wild who had normal sized telomeres.

Telomeres are important during genetic replication. During replication, DNA is unable to replicate exactly leaving a small portion of the sequence exposed. It is here that telomeres bind the exposed segment in essence protecting the chromosome and preventing a triggering of multiple DNA repair pathways. Significantly, eukaryotic cells are unable to sustain telomeres for endless time and as such they are worn down little by little after each round of DNA replication, eventually wearing away. Each time a cell divides, these telomeres shorten. When they become critically short, cells can no longer divide, leading to cellular senescence or programmed cell death (apoptosis). This is an important factor as no cell can replicate forever, as a result no tissue can maintain its exact architectural properties forever, unless specifically guided to do so.

The important factor about the different strains of mice and their telomeres that Weinstein discovered was that those with longer telomeres (specific, controlled growth in a lab) actually sustained more tissue based problems and had a higher rate of tumours. This is a very interesting result as it counters the logical thought that those who are bred specifically would be better adapted as a result of this specificity. Clearly, not the case for a variety of potential reasons:

1. Increased Cell Proliferation: Mice with longer telomeres may have cells that proliferate more rapidly. While this can be advantageous in certain situations, such as wound healing, it can also increase the risk of errors during cell division, leading to a higher likelihood of rogue cells replacing healthy ones that can lead to tissue dysfunction and tumour formation. This is the basis of the proliferation of cancer but also is the basis of tissue based injuries, particularly after an initial tissue insult. This is an important consideration in throwing related injuries as all of them occur as a result of continued stressors that leads to biological accommodation.

2. Immune System Dysfunction: Longer telomeres might be associated with alterations in the immune system. Dysfunctional immune responses can lead to increased susceptibility to infections, autoimmune disorders, and chronic inflammatory conditions. Chronic subclinical inflammation is the basis of tissue breakdown and impaired regeneration. This is significant in the discussion of throwing related elbow injuries when you consider how often the athlete is throwing.

3. Tissue Regeneration: Longer telomeres may initially enhance tissue regeneration capacity, but this can also lead to uncontrolled cell growth and tumor formation if regulatory mechanisms are compromised.

4. Age-Related Changes: Telomere length is also associated with biological age. Longer telomeres may exacerbate the progression of age related diseases by promoting cellular senescence and inflammation. It must be noted that biological age is different than chronological age. Chronological age progresses as a result of time, whereas biological age progresses as a result of impaired cellular proliferation, impaired tissue regeneration and the capacity to deal with stress.

The story of the mice discovered by Weinstein sheds light on the concept that there are consequences to having significant early specific adaptive advantages that go against the evolutionary process. By having long telomeres those mice would have a large capacity to replace damaged tissue, however, with this comes the risk of significant alterations over time in the healing and regeneration of cellular content (like ligaments in the elbow) especially when having to deal with large external variations that cause “stress”. This leads to long term accumulated damage that stays under the surface and may otherwise go undetected. Thus, what makes you adaptable can also make you non-adaptable and has varying consequences from tissue quality to overt maladaptive disease/injury processes.

Natural Selection Creates Trade-Offs

Paramount to evolutionary biology is Natural Selection. Among other things, natural selection is a process by which heritable traits conferring survival and reproductive advantage to individuals tend to be passed on to succeeding generations and become more frequent in a population, whereas other less favourable traits tend to become eliminated as they do not provide any progressive advantage.

One of the major insights of Darwin’s now vastly accepted theory is that over time as evolution “accumulates” small increments of benefit in successive generational offspring that the design of an organism always involves compromises or evolutionary trade-offs – one between youth and senescence - you can’t have both!

Senescence - refers to the process of aging in living organisms, particularly in cells, tissues, and ultimately the whole organism. It involves a progressive gradual decline in physiological functions and an increased susceptibility to disease, ultimately leading to death. Senescence can occur at various levels, including cellular senescence, which is the permanent cessation of cell division, and organismal senescence, which encompasses the overall decline in functioning and vitality of an organism as it ages. It's a complex biological phenomenon influenced by genetic, environmental, and lifestyle factors.

It is important to understand that senescence although referring to aging is not related solely to chronological age, which is simply the passage of time, it refers more specifically to biological age which is determined by the internal status and the efficiency of all physiological systems within the human. Regardless of chronological age, those with internal system dysfunction will have a higher biological age leading to potential system inefficiency and breakdown.

The interpretation is that the process of natural selection makes an asymmetrical “choice” early in life to maximize so called Darwinian fitness however, this comes at a downside cost as it exposes the organism to potential maladaptation to the same repeated stresses later in life and therefore, earlier decline as undesirable traits would not be able to be selected against. This means that there is an open window of time during development whereby we are prone to many external influences early in life that could lead to less than favourable consequences in the future.

George Williams published one of the most influential papers on evolutionary senescence. Williams proposed that biological aging was caused by the combined effect of many variable genes that each had a beneficial effect in youth but also had an adverse side effect in older age. Therefore, traits that have beneficial effects early in life will tend to spread, even if they are inseparably coupled with deleterious effects that manifest later in life.

Although his thoughts are more than 60 years old, they do have very interesting and relevant consequences for what we see today in athletic performance. Could this be associated with some of the decline we see? Could this be associated with the current arm epidemic we see in MLB?

Williams is describing the gradual breakdown and loss of internal system specific behaviours over time. This has been specifically and repeatedly shown and quantified in studies in tissue of fibroblastic nature (such as ligaments). This has direct effects on tissue behaviours like, elasticity, stiffness, regeneration and can ultimately lead to dire consequences. From this as well, we can surmise that these system behaviours would occur much faster in very stressful external environments and biological age would increase in otherwise young athletes as allostatic load increases. Athletes would potentially enter the period of senescence far earlier as a result of the trade-off between vigor and longevity.

How Does This Relate to Elbow Injuries?