Autophagy is Protective Against Hematopoietic Stem Cell Aging

Hematopoietic stem cells in the bone marrow give rise to red blood cells and immune cells. Like all stem cell populations, they become increasingly dysfunctional with age, however. In part this is damage to the stem cells themselves, but a sizable portion of the problem results from age-related damage and change in the niche of supporting cells that is needed to maintain a stem cell population. It is hoped that restoring stem cell function in older individuals will go a long way towards producing slowed aging and improved health. At present the research community is progressing towards this goal one stem cell population at a time, but it seems plausible that some discoveries will be broadly applicable to all stem cells in the adult body.

Aging of the hematopoietic system promotes various blood, immune, and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction. Autophagy is central for the benefits associated with activation of longevity signaling programs, and for HSC function and response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional. However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown.

Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche. We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment.

Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.



looks like 24hours to autophagy activation in mice, but how long for humans?

Posted by: erasmus at September 12th, 2023 7:55 AM


The time it takes for autophagy to be activated can vary depending on several factors, including an individual's overall health, diet, and lifestyle choices. Autophagy is a dynamic process that occurs at different levels in the body continuously, but it can be upregulated or enhanced in response to specific triggers. Here's a general timeline for some common autophagy triggers:

Fasting: Autophagy can start to increase after several hours of fasting. Studies suggest that a period of 12 to 24 hours of fasting can lead to significant activation of autophagy in various tissues. However, the exact timing may vary between individuals.

Exercise: Physical activity can stimulate autophagy, but the timing can differ based on the intensity and duration of the exercise. Some studies suggest that autophagy may be enhanced during and immediately after exercise, particularly during aerobic activities like running or cycling.

Diet: Low-carb or ketogenic diets may promote autophagy relatively quickly, within a few days to a week as the body adjusts to using ketones for energy. Caloric restriction diets may also start to stimulate autophagy within a day or so of reduced calorie intake.

Sleep: Quality sleep is essential for autophagy, and the process occurs predominantly during the nighttime sleep cycle. Ensuring you get a full night's rest on a regular basis is crucial for maintaining healthy autophagic activity.

Stress and Hormonal Factors: Stressors like heat or cold exposure, oxidative stress, and hormonal fluctuations can activate autophagy relatively quickly, within minutes to hours in some cases.

mTOR inhibition drugs and supplements:
Rapamycin and spermidine can induce autophagy within a few hours of administration. By inhibiting mTOR, they remove the inhibition on autophagy and allow it to proceed.

It's important to note that the degree of autophagy activation can vary among individuals, and the timeline can be influenced by factors like age, genetics, and overall health. Additionally, chronic or long-term autophagy is essential for maintaining cellular health, so these short-term triggers should ideally be part of a consistent and balanced lifestyle rather than sporadic events.

Posted by: Jones at September 12th, 2023 12:10 PM
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