Did Scientists Just Find a Way to Reverse Aging?

Looks like Bryan Johnson may soon have to add a new supplement to his anti-aging stacks: Trio, the protein of youth! 

Are we about to see elderly biohackers leaping around like spiderman? Silicon valley self-experimenters will be paying special attention to New York neuroscientist Brian McCabe’s latest research publication. Published in the journal Cell Reports, McCabe and his team say they have found the molecular key to reversing decline of the connections between muscles and neurons that slow us down as we age. 

As we age, the connection between our nerves and muscles, called neuromuscular junctions, doesn’t work as well. Think of it like an appliance’s plug and socket: the muscle is the appliance, the motor neuron is the power cable and plug, and the brain is the socket. This connection is vital for muscles to work, as the motor neuron sends electrical signals to the muscle, telling it when to contract.

With age, the “plug and socket” can become loose or damaged, making it harder for the signals to get through clearly. This leads to muscle weakness, slower reflexes, and difficulty with coordination. It’s a normal part of aging, but understanding this connection is important for finding ways to maintain muscle health as we get older. 

Understanding the process of aging is all well and good, but what if while you were researching it you found a way to reverse the decline? Well, it looks like scientists at Columbia University’s Brain Mind Institute have done just that.

In their research paper, published in Cell Reports, Dr. Brian D. McCabe and his team share what could be the secret to everlasting muscular youth: a protein called Trio. Trio is the guardian of neuromuscular junctions, playing a pivotal role in maintaining the delicate “plug and socket” connection between nerves and muscles.¹ In humans, Trio is important for proper nervous system development and neuromuscular connection.² Luckily for these brain scientists, fruit flies also share this crucial protein, allowing the researchers to to see if they could turn back time by artificially boosting Trio levels and preventing the age-related damage to these connections in flies.

Loose connections

As we age, both flies and humans experience a decline in muscle strength and function.^3-5 This can be attributed to changes in the connections between our nerves and muscles, called neuromuscular synapses. These connections weaken with age with large bulb-like structures, where neurotransmitters (chemical messengers) are released, fragmenting and shrinking. These changes are thought to be related to the protein framework that supports the synapse. Scientists knew that the protein scaffolding complex that holds together the internal skeleton of the neuron declines with age. McCabe and his team took a deeper look into what keeps these delicate structures standing.^6,7

The weakening “plug and socket”

Why does aging take a toll on the vital “plug and socket” connections? It is a result of multiple cellular changes: mitochondria, the powerhouses of cells, become less efficient, oxidative stress damages cellular components, and a whole other host of complications adds fuel to the fire. Additionally, accumulated protein and DNA damage overtime, exacerbates the vulnerability of these connections.

With these damaging changes, the neuron’s ability to communicate also diminishes, partly due to a decline in neurotransmitter release. This critical process, essential for transmitting signals between nerve cells, becomes less efficient over time due to a combination of factors. 

These intricate cellular processes collectively lead to a weakened “plug and socket” connection and neurotransmitter release, ultimately showing up as reduced muscle strength, impaired coordination, and increased fatigue.

Unveiling the mechanism

The researchers first confirmed that neuromuscular synapses in aging fruit flies were broken down. They observed larger nerve endings splitting into smaller units with fewer neurotransmitter release sites. 

Next, they focused on neurotransmitter release. As the flies aged, their ability to release these chemicals declined. Flies engineered with boosted Trio levels maintained their ability to release neurotransmitters- even under intense stimulation. This hinted that Trio preserves communication between nerves and muscles, likely contributing to the flies’ improved motor function.

Trio turns back time

Other researchers had already shown that the Trio protein helps a neuron’s skeleton to hold its shape.¹ When the Brain Mind Institute scientists hunted for Trio at the neuromuscular junctions they found that older flies had only half as many Trio molecules as their younger relatives.

The researchers went a step further in their quest for answers, digging into the flies’ very DNA. This time they genetically modified the flies so that they could change how much Trio they had. Lowering Trio levels accelerated the deterioration of nerve-muscle connections, while flies with boosted Trio levels maintained strong, youthful connections even in old age. Remarkably, introducing a human version of Trio into these flies reversed the damage, even when introduced later in life. 

More Trio, more climbing

The researchers found that boosting Trio in middle-aged flies got them back on their legs and climbing, remarkably 76.3% better than their unboosted teammates. When they looked at how well these Trio boosted bugs neuron’s were working they found that Trio could delay the onset of age-related motor decline.

These findings offer a promising new avenue for research into potential therapies to combat age-related muscle decline in humans. By targeting Trio, researchers may be able to develop strategies to delay or even reverse muscle weakness associated with aging.

References

1. Banerjee, S. et al. (2024) ‘Trio preserves motor synapses and prolongs motor ability during aging’, Cell Reports, 43(6), p. 114256. doi:10.1016/j.celrep.2024.114256. 
2. Tao, T., Sun, J. and Zhu, M.-S. (2020) ‘The triple functional domain protein trio with multiple functions in the nervous system’, Journal of Neurology & Neuromedicine, 5(1), pp. 22–30. doi:10.29245/2572.942x/2019/1.1263. 
3. Ingram, D.K., London, E.D., Reynolds, M.A., Waller, S.B., and Goodrick, C.L. (1981). Differential Effects of Age on Motor Performance in Two Mouse Strains. Neurobiol. Aging 2, 221–227. https://doi.org/10.1016/ 0197-4580(81)90025-7.
4. Leversen, J.S.R., Haga, M., and Sigmundsson, H. (2012). From Children to Adults: Motor Performance across the Life-Span. PLoS One 7, e38830. https://doi.org/10.1371/journal.pone.0038830.
5. Hunter, S.K., Pereira, H.M., and Keenan, K.G. (2016). The Aging Neuro- muscular System and Motor Performance. J. Appl. Physiol. 1985 121, 982–995. https://doi.org/10.1152/japplphysiol.00475.2016.
6. Hakeda-Suzuki, S., Ng, J., Tzu, J., Dietzl, G., Sun, Y., Harms, M., Nardine, T., Luo, L., and Dickson, B.J. (2002). Rac Function and Regulation during Drosophila Development. Nature 416, 438–442. https://doi.org/10.1038/ 416438a
7. Neubrand, V.E., Thomas, C., Schmidt, S., Debant, A., and Schiavo, G. (2010). Kidins220/ARMS Regulates Rac1-Dependent Neurite Outgrowth by Direct Interaction with the RhoGEF Trio. J. Cell Sci. 123, 2111–2123. https://doi.org/10.1242/jcs.064055.