Nardilysin and OGDHL: Two Rare Genes That Add a Piece to the Brain Aging Puzzle

How can we understand brain aging that takes decades? Sometimes the best way is to learn from young patients who show it in an accelerated form. An international team from Texas Children's Hospital and Baylor College of Medicine, led by Prof. Hugo Bellen, followed two young patients with severe neurodegenerative symptoms that no one could diagnose. They published in Neuron findings that not only solved the mystery but revealed a combination of mechanisms that may also help understand normal brain aging.

The Patients: Two Cases, One Diagnosis

Two teenagers, from different parts of the world, came for genetic testing with similar symptoms:

• Inability to walk
• Inability to eat independently
• Loss of speech
• Progressive reduction in brain size (acquired microcephaly)
• Gradual breakdown of motor and cognitive functions

Both functioned normally at birth, then gradually declined throughout childhood and adolescence. Standard genetic tests showed something strange: both patients carried mutations in different genes. One in NRD1 (nardilysin), the other in OGDHL. No test had previously linked these two genes.

The Connection: Both Disrupt the Same Metabolic Pathway

The Bellen team used a multi-pronged approach—examining what happens when the genes are removed from fruit flies, mice, and human cells in the lab. The findings coalesced into a single story:

1. NRD1 (nardilysin) resides in the mitochondria. It functions as a mitochondrial co-chaperone, meaning an auxiliary protein that assists in the proper folding of other proteins. Its central role here: helping fold α-ketoglutarate dehydrogenase (OGDH), a key (rate-limiting) enzyme in the Krebs cycle.
2. OGDHL is a paralog of OGDH, meaning a close gene from the same family that encodes a similar enzyme. Therefore, damage to OGDHL (in the second patient) and damage to OGDH folding (when nardilysin is absent in the first patient) lead to the same failure: cells cannot process α-ketoglutarate properly.
3. α-ketoglutarate accumulates in cells. Under normal conditions, it is further converted in the Krebs cycle. When it accumulates, it activates mTORC1—the cell's "growth switch."
4. mTORC1 activates protein synthesis and halts autophagy (cellular cleanup). This is disastrous for neurons, which depend on autophagy to stay clean.
5. Neurons accumulate waste, lose function, and eventually die. Neurodegeneration.

Two different genes, one pathway. And once the pathway is understood, a fundamental treatment possibility opens up.

The Solution: Rapamycin Alleviated Symptoms

Rapamycin (Sirolimus) is a well-known drug that suppresses the mTORC1 pathway. It is used in organ transplants as an immunosuppressant. The researchers asked: if the problem in patients is overactive mTORC1, would rapamycin help?

They tested this in fruit flies with the mutations. The result was encouraging:

• Untreated flies died young from loss of neural function
• Flies treated with rapamycin showed partial reversal of degenerative symptoms
• Neurodegeneration slowed, and some function was preserved for a longer period

This is not yet human medicine, but it is a proof of principle: suppressing mTORC1 with rapamycin (or partially restoring autophagy) partially slows the neurodegeneration caused via the NRD1/OGDHL pathway.

Why Might This Be Relevant to Everyone?

These patients are very rare, but the pathway they reveal is not rare. The researchers suggest that the finding links the rare disease to broader brain aging processes, and from the general aging literature, a similar picture emerges:

• Mitochondrial function declines with age and can impair Krebs cycle enzymes, including OGDH
• Overactivity of mTORC1 is considered a hallmark of aging and has been linked in studies to Alzheimer's and Parkinson's diseases
• Poor autophagy in older adults allows brain waste to accumulate

In other words: the extreme symptoms of the patients may show in exaggerated form part of what occurs in normal aging, although this specific study did not prove this link for normal aging—it studied a rare genetic disease. The connection to aging is a hypothesis based on additional aging studies, not a direct finding of this work.

Rapamycin as a Longevity Drug?

This connection explains some of the great interest in rapamycin as a potential longevity drug. In mice, rapamycin is one of the few drugs that has consistently extended lifespan in controlled studies. The presumed reason: it suppresses mTORC1, allows autophagy to work, and slows the accumulation of waste in tissues, including the brain. It is important to emphasize that this is broad background on rapamycin and the mTOR pathway, not a finding of the NRD1/OGDHL study itself.

But rapamycin is not without drawbacks:

• Suppresses the immune system. Risk of infections
• May impair glucose and lipid metabolism
• Long-term effects in humans are still unclear

In human studies, the approach of low-dose, intermittent rapamycin (e.g., once a week instead of daily) is being examined as a way to achieve benefits with fewer side effects. This is an active area of anti-aging research, not an approved treatment.

What Can Be Done Without Medication?

Even without rapamycin, it is possible to encourage autophagy and reduce mTORC1 activity through natural means:

• Intermittent fasting: Restricted eating windows (e.g., 16/8 or 18/6) promote autophagy
• Physical activity: Especially resistance training, balances mTORC1 (temporarily increases it but improves overall regulation)
• Moderate caloric restriction: A modest reduction in calories lowers mTORC1 activity
• Not excessive protein: Intake of about 1.2-1.6 grams per kg is sufficient for most of us. Continuous excess protein constantly activates mTORC1
• Green tea and coffee: Contain compounds linked to reducing mTORC1 activity (EGCG, chlorogenic acids)

Research Implications

The discovery by Bellen and his team opens the door to further studies. If NRD1 and OGDH/OGDHL are the focus, perhaps it will be possible to develop drugs more specific than rapamycin that target this pathway. Research is ongoing on molecules that stabilize OGDH without globally suppressing all mTORC1 activity.

This is an example of what is good about medical research in the modern era: delving into rare diseases sometimes leads to insights that may also help understand common processes.