Lipofuscin, the toxic waste of aging

lipofuscin

As we and other organisms age, the means of dealing with intracellular junk decline. Autophagy, for instance, is a prime method that cells have of ridding themselves of and recycling structures and proteins that have passed their expiration date. Aging organisms lose the ability to activate autophagy as strongly as they could when younger. One consequence of this is the accumulation of lipofuscin, the toxic waste of aging.

To explain what lipofuscin is, one could do no better than to quote from an article in Science:

Lipofuscin is membrane-bound cellular waste that can be neither degraded nor ejected from the cell but can only be diluted through cell division and subsequent growth. The fate of postmitotic cells is to accumulate lipofuscin, which as an “aging pigment” has been considered a reliable biomarker for the age of cells such as neurons and, by extension, their hosts. In the aging human brain, deposits of lipofuscin are not uniformly distributed but are concentrated in specific regions of functional interest. The prevailing thought is that the major source of lipofuscin is incomplete lysosomal degradation of damaged mitochondria. Accumulating evidence suggests that lipofuscin is not benign but can impair the functioning of seemingly unrelated cellular systems, including the ubiquitin/proteasome pathway. A damaging feedback loop of lysosomal and proteasomal inhibition may occur as lipofuscin accumulates, leading to what has been appropriately named a “garbage catastrophe.” Reversing this catastrophe presents a formidable challenge.(1)

It seems clear enough that preventing the accumulation of lipofuscin ought to be a target for anti-aging strategies. How can that be done?

First, let’s take a closer look at how lipofuscin accumulates. Decreased autophagy is a major cause, and lipofuscin in turn limits autophagy in a descending spiral.(2)

Iron is key in the formation of lipofuscin

It will not by now come as a surprise that iron is involved in the accumulation of lipofuscin, and in fact iron forms a major part of this toxic waste.(3)

Key points from this last citation:

  • Iron accumulates in lysosomes (autophagic vessels)
  • Hydrogen peroxide reacts with iron to form hydroxyl radicals to form lipofuscin
  • Lipofuscin is not degradable
  • Formation rate of lipofuscin is inversely related to species lifespan
  • Lipofuscin degrades autophagic capacity
  • This causes declining removal of damaged structures and proteins

Iron is key in the formation of lipofuscin.

Free iron, which is iron not locked down by ferritin or other iron storage molecules, is the kind that does damage. But the amount of free iron appears to be a function of the amount of total iron, so the less iron in the system altogether, the lower the rate of lipofuscin formation.

Lipofuscin and the iron in it is a major source of oxidants and can lead to cells becoming senescent.(4) This is probably why the presence of senescent cells causes a system-wide increase in oxidative stress.

How to prevent/remove lipofuscin, the toxic waste of aging

There seems to be a very limited number of ways to deal with it.

Long-term treatment with acetylcarnitine (ALCAR) significantly reduced the amount of lipofuscin in the brains of old rats.(5)

Zinc deficiency leads to lipofuscin accumulation.(6) Zinc supplementation would presumably help.

Revving up the autophagic mechanism may be of help, and intermittent fasting as well as intermittent fasting enhancers will do this.

Finally, and to my mind the most important method of avoiding the accumulation of lipofuscin, keep iron levels low; this can be done with blood donation, iron chelators, and inhibition of iron absorption with tea, coffee, and red wine, as well as a low-iron diet rich in plant polyphenols.

 

 

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22 Comments

  1. M Braivo says:

    Fasting, blood donation, lifting, and targeted supplementation. You continue to hone in on the essentials that can really transform men’s lives. I don’t think this can be repeated enough. Men need to hear it.

  2. Neguy says:

    Are you planning to start taking acetylcarnitine?

  3. Philomathean says:

    I gave blood today. My finger was pricked before the donation to measure hemoglobin (15.5 g/dl) and iron (47 %).

    I’m curious about what the iron percentage means in relation to the ongoing discussion at this blog.

    An aside: I felt a pang of guilt donating blood for a selfish motive. I wasn’t there to help anyone but myself. The lady said the donation will be used within three days at the children’s hospital. I planned to donate twice a year to control iron but now I’ll donate three times a year and donate platelets a few times a year as well. That way it feels more like a win/win situation.

    • P. D. Mangan says:

      What you refer to as iron percentage is your hematocrit, which is the percentage of your total blood volume that is composed of red blood cells. Blood banks don’t directly measure iron, so in reality you could in theory have a high iron (ferritin) level. Or a low one for that matter. Hemoglobin and hematocrit aren’t affected (lowered) unless iron gets quite low, and are unaffected by high values. According to the study I posted, the average twice-yearly blood donor has a ferritin around 50, solidly in the healthy (low normal) range.

  4. Nathan says:

    It’s recently dawned on me that I should time my zinc supplementation for a meal without chelators (turmeric, coffee,tea,chocolate) as they’ll chelate zinc as well as iron. Also, if supplementing with zinc it competes with copper to be absorbed so you need to supplement with copper as well, as a deficiency will lead to lower production of the important enzyme copper dismutase.

    • P. D. Mangan says:

      Nathan, the zinc effect on lowering copper doesn’t come about unless one takes 50 mg or more of zinc a day for several months, which is a hefty dose only used for the obviously zinc deficient. One should probably be under a doctor’s care if taking that much zinc. Lower, supplement-style doses shouldn’t affect copper.

    • Rob H says:

      Hi Nathan, yes I realised the same thing too re timing zinc supplements away from foods containing phytates/ chelators. However, I’m assuming this equally applies to any other mineral supplements you may take, ie: magnesium, chromium, and also nicotinamide (Vit B3). I just take them first thing in the morning now, away from all foods except a teaspoon of butter to provide Vit K2 + fat for absorption purposes.

  5. ted says:

    https://groups.google.com/forum/#!topic/sci.life-extension/ccoCPIdIWA4
    Lipofuscin can be eliminated from cells, according to this study

  6. RT says:

    Hey PD,

    Was reading up on lipofuscin and came across this from 1975 – https://www.ncbi.nlm.nih.gov/pubmed/1106435

    Lipofuscin removal at a very small rate by microglia cells appears to occur normally in the ageing animal, but is greatly enhanced by centrophenoxin. Cessation of drug application does not stop the process of removal at once and the process continues as far as we can judge by our experiments for several weeks without further drug application. Even 30 mg/kg per day were found to be sufficient to initiate and sustain lipofuscin removal.

    I read about centrophenoxin being a nootropic, have you perhaps tried it at some point?

  7. Ted says:

    PD, have you looked into DMAE for dissolving/removing lipofuscin?
    https://raypeatforum.com/community/threads/dmae-for-lipofuscin-removal.807/

    Interested to hear your thoughts. I read SENS foundation is funding/working of a way to synthesize exogenous lipofuscin, then it will be possible to do actual experiments on dissolving it.

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