MSDC-0160 - ITP 9% Increase in Mouse Lifespan (Males)

#1

MSDC-0160 extends lifespan by promoting a metabolic shift towards alternative fuel sources like ketones and beta-oxidation, which can protect cells from age-related decline and disease, especially neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, and potentially aging in general. As a mitochondrial pyruvate carrier (mTOT) modulator, it facilitates this energy reorganization by increasing ketogenesis and beta oxidation, supporting energy homeostasis. This metabolic rerouting is associated with improved motor function, reduced neuroinflammation, and better maintenance of glucose metabolism in certain brain regions, all contributing to a longer, healthier life.

How MSDC-0160 works to extend lifespan:

  • Modulates Energy Metabolism:

MSDC-0160 inhibits the mTOT protein, which alters cellular energy use.

  • Increases Ketogenesis and Beta-Oxidation:

By shunting metabolism, the drug boosts the production of ketones and the burning of fatty acids for fuel.

  • Supports Energy Homeostasis:

This shift in fuel source helps maintain stable energy levels within cells, a crucial aspect of healthy aging.

  • Neuroprotection:

The metabolic changes induced by MSDC-0160 provide neuroprotective benefits, improving conditions related to aging.

  • Improved Glucose Metabolism:

In non-diabetic individuals with mild Alzheimer’s, the drug helped maintain glucose metabolism in key brain areas, preventing decline seen in placebo groups.

  • Protection Against Age-Related Diseases:

Preclinical studies have shown it can extend lifespan in mice with accelerated aging and protect against age-related damage to lungs and the vascular system.

Applications and Future Directions:

  • Neurodegenerative Diseases:

The neuroprotective effects make MSDC-0160 a potential candidate for treating neurodegenerative diseases like Alzheimer’s and Parkinson’s.

  • Accelerated Aging:

Its ability to prolong life in accelerated aging models suggests it could be used to treat human conditions that cause premature aging.

  • Metabolic Health:

By improving insulin sensitivity and counteracting metabolic issues, it could play a role in promoting healthy aging.

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#2

Potential side effects:

MSDC-160 (a prototype drug related to thiazolidinediones) may have side effects such as mild peripheral edema and an increase in aggregated alpha-synuclein levels in certain Parkinson’s disease models. It has also been associated with potential off-target effects seen with other thiazolidinediones, like mitochondrial dysfunction and cardiotoxicity, although specific side effects for MSDC-160 require more extensive clinical trials.

Specific Side Effects and Clinical Context

  • Peripheral Edema:

In a clinical trial for patients with mild Alzheimer’s disease, mild peripheral edema (swelling) was reported in a small percentage of patients receiving MSDC-160.

  • Increased α-Synuclein Aggregation:

In animal models for Parkinson’s disease, MSDC-160 was found to increase the levels of aggregated alpha-synuclein, a protein implicated in the disease.

Potential Risks Related to its Class (Thiazolidinediones)

MSDC-160 belongs to a class of drugs called thiazolidinediones (TZDs), which can have broader risks:

  • Cardiotoxicity:

TZDs have been linked to an increased risk of cardiovascular adverse events, including congestive heart failure and myocardial infarction.

  • Mitochondrial Dysfunction and Oxidative Stress:

These drugs can induce mitochondrial dysfunction and oxidative stress, potentially contributing to cardiovascular and liver problems.

What This Means

  • Mild and transient effects:

The edema observed in clinical studies was generally mild and resolved without intervention.

  • Need for more research:

The increase in α-synuclein in animal models suggests a need for further research to understand its implications and if it translates to human patients.

  • Class-dependent risks:

The potential risks associated with TZDs, such as cardiotoxicity, may also apply to MSDC-160, though the specific risk profile for this particular drug requires more extensive clinical trials.

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#3

This one looks interesting. Anyone have any experience with this?

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#4

Can you link to the ITP MSDC-160 trial?

In the (AI?) writeup, reference to accellerated aging phenotype of mice is not encouraging. MK’s 900 day rule applies.

The fact that MSDC-160 is in the class of TZD drugs doesn’t by itself mean much. There is mention of cardiotoxicity of this class of drugs, but that’s hardly uniform. There is no evidence of cardiotoxicity of one member of that class: pioglitazone. The only increase of HF is due to edema, not toxicity. Instead, pioglitazone is largely cardioprotective as multiple studies have shown - see for example my post, where I cite two papers looking at this issue:

In fact, if examining the TZD class agents, I’d be curious about ITP looking at pioglitazone. Because if both pioglitazone and MSDC-160 belong to roughly the same class of drugs, the lifespan effects of pioglitazone might be of interest.

There are more papers addressing pioglitazone and AD (to be seen in the same thread I referenced above), but as I posted in the Parkinson’s Disease thread, pioglitazone failed against PD in a trial. How MSCD-160 might affect AD and PD therefore is not clear simply based on the drug class.

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#5

The information about the ITP experiment with MSDC-160 can be found here:

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