This doesn’t mean as we get older our bodies completely betray us. Our work demonstrates that aged mice are capable of mounting the appropriate disease tolerance response
Janelle Ayres
Foxo1 and Trim63 Proteins Drive Age-Dependent Cardioprotection
The researchers discovered that young survivors were protected by a protein called Foxo1 and a gene it regulates, called Trim63. When Foxo1 turns on Trim63 expression, it stimulates the production of the protein MuRF1, which then promotes the breakdown of larger molecules into usable energy in cardiac and skeletal muscle cells. In young survivors, increased expression of Foxo1 and Trim63 created a cardioprotective effect, blocking multi-organ damage and preventing the cardiac remodeling seen in their deceased counterparts. Surprisingly, Foxo1, Trim63, and MuRF1 had the opposite effect on older survivors.
The researchers saw that Foxo1 deletion improved survival of older mice and decreased survival of younger mice. And in normal conditions, older survivors recovered with enlarged hearts, showing that the very same mechanism causing younger mice’s demise had enabled their survival. “Our findings reveal that young and aged hosts can have distinct disease trajectories when exposed to the same pathogens,” says co-first author Justin McCarville, a former postdoctoral researcher in Ayres’ lab. “Despite this difference, we show that involvement of the same molecular pathway determines survival, but it leads to opposite outcomes, depending on age. This raises broader questions about how disease may manifest differently across age groups and underscores the potential need for therapies that are tailored to the unique physiology of different ages.”
Age Influences Disease Trajectories Through Molecular Pathways
The concept of antagonistic pleiotropy helps make sense of these seemingly surprising findings. Antagonistic pleiotropy is a theory first proposed in evolutionary biology that suggests some traits that are beneficial in youth can incur costs later in life. Getting through the reproductive years of youth is the evolutionary priority, so biology will often optimize those years at the expense of an organism’s health down the line. “We aren’t doomed, though—this doesn’t mean as we get older our bodies completely betray us,” says Ayres. “Our work demonstrates that aged mice are capable of mounting the appropriate disease tolerance response, and we have initiated lines of investigation in our lab to figure those mechanisms out.”
Implications for Age-Specific Therapies Against Sepsis and Infections
These findings may guide the development of more effective treatments for sepsis, and potentially other infections, diseases, and disorders. Medications could be developed that are age-specific, targeting different disease tolerance mechanisms in younger and older patients. This strategy would improve outcomes for both age groups, ushering in an exciting new era of tailored therapeutics that pathogens will not evolve resistance to, helping to overcome the global crisis of antibiotic resistance.
Source: Salk Institute