LifeOmic: What does it mean, to rejuvenate the brain or “make an old brain young again,” on the cellular level? What is the most compelling research you’ve seen on interventions that delay or reverse brain aging?

Shelly: My lab mainly studies the hippocampus, a brain region crucial for spatial and episodic memory, that is, the memory of autobiographical events. Young blood and other systemic manipulations, such as exercise, caloric restriction and metformin (a type II diabetes drug), seem to revamp the aged hippocampus in two main ways.

Synaptic Transmission, NIH.

First, these treatments boost neuronal communication during learning (synaptic plasticity, evidenced through electrical recordings). At the molecular level, the treatments stimulate the production and/or activation of proteins that support synaptic plasticity, like CREB.

Editor’s Note: CREB (cAMP response element-binding protein) is a transcription factor capable of binding DNA and regulating gene expression. CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain. There’s evidence that cognitive stimulation, exercise and intermittent fasting (in mice) can enhance brain-derived neurotrophic factor (BDNF) and serotonin signaling, which in turn activate transcription factors like CREB that regulate gene expression involved in neural plasticity, stress resistance and cell survival.

These interventions also lower global brain inflammation, which is thought to benefit cognition.

By far the most compelling research I’ve seen in this area is related to exercise, caloric restriction and young blood. Exercise has by far the most evidence for benefits in aged humans. Caloric restriction as an intervention is relatively hard for humans to follow for long periods of time, and I haven’t yet seen a well-done human study in that domain. There’s actually some controversy on whether caloric restriction works in non-human primates in terms of increasing healthspan (the length of healthy life). Young blood hasn’t yet been rigorously tested in humans for its anti-aging effect (there are some iffy “trials” going on), though a recent study using it for Alzheimer’s disease didn’t show significant benefits. The eventual goal is to isolate out specific “pro-youth” factors from young blood and administer those in a concentrated form.

LifeOmic: How does the aging brain look different, metabolically or on the cellular level, than the young brain?

Shelly: The aged brain looks different in a few main ways (blog post here). One, the cell’s main energy factory, the mitochondrion, declines as we age both in numbers and function. Disrupted brain metabolism has been linked to Alzheimer’s disease, but its role in normal age-related memory decline is less clear. Aged neurons also have trouble sensing nutrients in their environment. This is especially true for glucose, which normally is the brain’s main energy source.

Editor’s note: This is where intermittent fasting comes in as an interesting intervention to improve nutrient signaling or insulin sensitivity.

Aged neurons in the hippocampus and prefrontal cortex also have fewer synapses, although the total number of neurons doesn’t seem to change much with age. Finally, aged brains have little to no neurogenesis and increased inflammation, though if and how these processes contribute to age-related memory decline remains unclear.

Editor’s Note: Animal model research suggests that intermittent fasting, or reduced meal frequency, can increase insulin sensitivity, improve cellular stress responses and reduce oxidative damage in the brain, in ways similar to the impacts of exercise.

LifeOmic: What is synaptic plasticity, and what are the potential ways we can preserve it in the aging brain?

Shelly: Broadly speaking, synaptic plasticity is the brain’s ability to strengthen or weaken connections between pairs of functionally linked neurons. Neurons form functional circuits through specialized nodes called synapses. The synapse is where one neuron talks to another.

One central idea in neuroscience is that learning activates select neurons. These neurons then form a clique of sorts. When one neuron reactivates (for example, when you want to retrieve the memory), there’s a much higher chance that others in that same circuit will also fire. In essence, the synaptic connections strengthen during learning. Similarly, synaptic strength can also weaken. The ability to change synaptic strength is called synaptic plasticity, and scientists believe it underlies our ability to learn and remember things.

I’ve already mentioned a few ways to preserve plasticity in the brain: aerobic exercise such as running and caloric restriction are both more “natural ways” to go about it. Young blood and (more promisingly) metformin represent a more pharmacological approach, which many researchers are focusing on.

LifeOmic: How can we stimulate neurogenesis in the aging brain? In your research and expertise, what interventions are promising (for humans) in stimulating neurogenesis?

Shelly: Running! I used to be a long-distance runner in grad school. I used it for stress management, but fell off the band wagon during my PhD. Later, in the lab, I actually looked at the brains of runner (mice given running wheels) versus sedentary mice (mice that live normally in shoebox cages, so they still scurry around normally). The effect of running on neurogenesis was so astonishing that I picked up running again.

That said, I need to stress that whether humans have neurogenesis or the birth of new neurons cells beyond childhood is debatable. A recent Nature study didn’t find any signs of new neurons in the brain of aged human donors (excellent News and Views here), so it’s possible that exercise and other neurogenesis-stimulating treatments are working in some other way to benefit the aging brain. My bet is on synaptic plasticity and increased blood flow.