What's new

Drug Reverses Age-Related Cognitive Decline Within Days

Lumetic

Lightweight
Joined
Sep 20, 2019
Messages
63
Likes Received
136

Summary: Short-term exposure to an experimental drug reverses age-related memory decline and cognitive deficits in mice. The drug, ISRIB, has previously shown beneficial effects in treating memory loss associated with TBI and other neurological disorders.

Source: UCSF


Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published December 1, 2020, in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough, Lasker, and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses — a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell — a potential sign of viral infection or cancer-promoting gene mutations — and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily — a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.

ISRIB May Have Wide-Ranging Implications for Neurological Disease

It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:
  • Frontotemporal Dementia
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis (ALS)
  • Age-related Cognitive Decline
  • Multiple Sclerosis
  • Traumatic Brain Injury
  • Parkinson’s Disease
  • Down Syndrome
  • Vanishing White Matter Disorder
  • Prion Disease
ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form — against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects — and more attractive as a potential therapeutic. According to Walter: “It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.



...................................

ISRIB works dandy fine in humans too. There is a distinct mental clarify, like Windex to the foggy glass of the mind.
Since resuming ISRIB, I've been able to lay off the afternoon dopamine jolt I needed to get through the day to stay productive.
Plus I'm just ...dare I say, smarter on ISRIB. It's fantastic.

ISRIB looks like a linked dimer of the old nootropic Meclofenoxate (Lucidril, also known as centrophenoxine).
I have nearly zero concerns about safety or it's still 'experimental' status.
The issue with ISRIB is that it isn't soluble in SFA,...but someone may have found the answer. :)

My hope is that the dampening of the chronic hyperactive stress response isn't limited to initially neuronal and now certain immune cells.
There are several types of cells in this old warhorse that are stressed (lmao), and how wonderful it would be if ISRIB could press the rest set switch on all of then.
 

edarrin

Super Heavyweight
Joined
Nov 27, 2002
Messages
254
Likes Received
49
Interesting candidate. Let's see if it works in humans. Many things that work in mice do not in humans as I'm sure you're aware
 

Lumetic

Lightweight
Joined
Sep 20, 2019
Messages
63
Likes Received
136
Interesting candidate. Let's see if it works in humans. Many things that work in mice do not in humans as I'm sure you're aware

Works fine in humans. I've been using it off and on for a couple of years. Previously it was injected IM, dissolved in DMSO, and that mostly sucked, but the drug worked as intended. There is a new aqueous suspension, which is nearly perfect, 10mg/ml.

ISRIB is one of the 4 or 5 things I'd take for the rest of my life. Currently administering it every other day, for reasons of simplicity to be honest.
 

Lumetic

Lightweight
Joined
Sep 20, 2019
Messages
63
Likes Received
136
In for the follow, @Lumetic did you notice benefits soon after starting this?

I am aware of improved cognitive aspects by the 2nd or 3rd day. Perhaps these things occur sooner, but my awareness of such is as stated.
The drug is working immediately post injection, and will achieve some meaningful level of distribution within a few hours.

Generally, as a generic comment on humanity, changes in one's mind (thinking/perception/etc) typically range in degrees of elusivity.
Some people tune into subtle aspects sooner, and others never seem to grasp anything less than a hammer blow to the head.

ISRIB is the only nootropic that for me repeatedly produced unmistakable cognitive clarity (no brain fog or BS common with nootropics).
ISRIB addresses one particular aspect of cellular function...(or mis-function). If the ISR is hyperactive and chronic (aka running amuck), ISRIB should be helpful.


As far as I know Inno is the only outfit in the entire world making ISRIB as an aqueous suspension.
One might be able to scare up some ISRIB powder online, but good fucking luck doing anything useful with it.


ISRIB is a wonderful molecule, with some of the worst solubility properties one could imagine. 5mg/ml in DMSO, and even then the shit precipitates regularly....fugetaboutit. ISRIB will never be mainstream because the population wants a pill, and that isn't going to happen with ISRIB.
 

Provoked

Rookie
Joined
Oct 6, 2019
Messages
6
Likes Received
6
Works fine in humans. I've been using it off and on for a couple of years. Previously it was injected IM, dissolved in DMSO, and that mostly sucked, but the drug worked as intended. There is a new aqueous suspension, which is nearly perfect, 10mg/ml.

ISRIB is one of the 4 or 5 things I'd take for the rest of my life. Currently administering it every other day, for reasons of simplicity to be honest.
What was your dosing schedule and how long would the run be? You experience after coming off? Your experience on?
 

Lumetic

Lightweight
Joined
Sep 20, 2019
Messages
63
Likes Received
136
What was your dosing schedule and how long would the run be? You experience after coming off? Your experience on?

1cc per day (10mg). I run it for as long as I can, usually until I get tired of poking myself. Often I end up with EOD injection for a while, and then take a break until I know I need another tune up.
Any amount of time after the 2nd/3rd injection is just bonus. I live in a state of chronic stress,
and by the 3rd injection I feel like I think I should feel, clear mind, less procrastination (perhaps true motivation), stress is not crippling,
creativity is increasing, hell I don't even mind other humans (lol). I feel like a human being by the 2nd/3rd injection, as opposed to a high functioning puddle of mess. It's amazing really.

Coming off, there is no crash or anything. If no meaningful changes were mades in one environment while using ISRIB, ie., those pre-existng stressors are still present, then one slowly moves back to how they felt before they used ISRIB.
 

Kdawg

Heavyweight
Joined
Oct 30, 2012
Messages
148
Likes Received
94
Location
Vancouver
This post is in violation of the rules. You have been issued a warning
 
Last edited by a moderator:
Top