#1

MTOR like protein MANF mesencephalic astrocyte derived neurotrophic factor [ Homo sapiens (human) ]

Gene ID: 7873, updated on 10-Dec-2024 help cells clean.
MANF is found in all living things and humans.

Researchers at McMaster University have uncovered a previously unidentified cell-protective role of a protein, potentially paving the way for new treatments for age-related diseases and promoting healthier aging.

protein MANF helps cells manage toxic protein clumps, improving cellular health and potentially aiding treatments for age-related diseases like Alzheimer’s and Parkinson’s. Keeps cells healthy and working.

https://www.ncbi.nlm.nih.gov/gene/7873

https://scitechdaily.com/longevity-breakthrough-new-protein-discovery-could-be-the-key-to-healthier-aging/

But MANF is not easy to activate.

To activate Mesencephalic astrocyte-derived neurotrophic factor (MANF), the most common method is to induce endoplasmic reticulum (ER) stress within a cell, as this is a primary physiological trigger for MANF upregulation and secretion; essentially, when a cell experiences significant stress on its protein folding machinery, it starts producing more MANF to help manage the stress and protect against cell damage.

Key points about MANF activation:

  • ER stress pathway:

Conditions like high levels of unfolded proteins, oxidative stress, or calcium dysregulation can activate the unfolded protein response (UPR), leading to increased MANF expression.

  • Cellular mechanisms:

When ER stress occurs, signaling pathways involving transcription factors like ATF6 (activating transcription factor 6) are activated, which then stimulate the MANF gene expression.

  • Therapeutic potential:

Researchers are exploring ways to pharmacologically activate MANF for neuroprotective purposes, particularly in conditions like Parkinson’s disease where dopaminergic neuron loss is prominent, as MANF has been shown to protect these neurons from degeneration.

Potential limitations to consider:

  • Specificity:

While ER stress can activate MANF, it also triggers other cellular responses, so finding ways to selectively target MANF activation might be necessary for therapeutic applications.

  • Intracellular localization:

MANF is primarily localized within the ER lumen, so its direct activation by extracellular means might be challenging.

So… I guess we stick with rapamycin and MTOR inhibition for now.

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#2

It’s a potential win if they can figure how to manipulate it.

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#3

From one of my favorite rapamycin podcasts:: The Dirty Drug and the Ice Cream Tub
Transcript - Matt Kaeberlein.
AVIR MITRA: It’s crazy 'cause even in med school, we had histology. And we would look at cells, and we would be trying to identify all the little pieces of the cell. And I would always see - like, you could see on one side, there’s this huge brown gunk just sitting there. And I’d be like, what is that? And I came to later learn that that’s just junk. It’s just deposit sitting there.

LATIF NASSER: And it’s like clogging up the function of the cell? Is that what’s going on?

AVIR MITRA: Yeah. That buildup of junk inside our cells over time makes us less efficient. It makes us sick. I talked to a bunch of scientists who study this. One of them, this guy, Matt Kaeberlein…

MATT KAEBERLEIN: I am a professor of laboratory medicine and pathology at the University of Washington.

AVIR MITRA: …Studied the effects of rapamycin on how long mice live.

MATT KAEBERLEIN: And we had this one mouse that kept going and going and going.

AVIR MITRA: They named him Ike.

MATT KAEBERLEIN: Ike, if we translated that linearly to human years, was about 125 years old - 130 years, yeah.

AVIR MITRA: Ike, wow.

MATT KAEBERLEIN: (Laughter) Right.

LATIF NASSER: But is this just, like, one super old mouse who you just made super older?

AVIR MITRA: No, no. That’s the thing. Like, there’s a government study that did this with a bunch of mice. These mice look and act younger. And it’s not just mice. Like, scientists have seen these kind of results in every species they try it on. So it’s yeast, worms, flies. They’re even doing a study to try it in pet dogs.

LATIF NASSER: Wow. And so all of this is just 'cause, like, rapamycin is just, like, clearing out all the junk?

AVIR MITRA: Yeah. Because all that junk basically causes aging and, over time, will kill us. Like Kaeberlein says, take something like Alzheimer’s disease, right? What is that? That’s tangles of proteins and junk that’s sitting around in your brain cells that’s getting in the way of, like, you having a thought.

MATT KAEBERLEIN: And there’s tons of data in mice that rapamycin can improve cognitive aging in mice. Starting rapamycin before the decline starts prevents the decline, and starting rapamycin after the decline starts partially reverses the decline.

AVIR MITRA: So you’re saying that rapamycin reverses Alzheimer’s in mice?

MATT KAEBERLEIN: That’s right.

AVIR MITRA: Wow.

And it’s not just Alzheimer’s. It’s, like, every marker of aging. It’s other diseases, too, like heart attacks, strokes and cancer…

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