Antioxidants inhibit basal autophagy and block the induction of autophagy by calorie restriction and other means. Because this effect inhibits the central mechanism of cell repair, it helps explain why dietary antioxidants have failed to deliver their expected benefits to health and longevity. The nature of the effect suggests prudent modifications to popular supplementation regimens.
Dietary antioxidant trials
show little benefit
A paper published a few weeks ago may help answer a long-standing question in aging research: Why have treatments that protect cells from oxidative damage produced so little net benefit?
It seems reasonable to expect benefits from increasing antioxidant protection in cells. Reactive oxygen species (ROS) damage cell components — especially mitochondria — and elevated ROS levels can shorten life, causing cancer, heart disease, neurological damage, etc. Dietary interventions successfully reduce ROS levels, hence the damage caused by oxidative stress, by increasing antioxidant activity in cells (for example, by elevating levels of antioxidants like vitamin E, superoxide dismutase, and α-lipoic acid).
Surprisingly, though, the well-studied dietary antioxidants have delivered little, no, or negative benefit in reducing age-related disease and mortality. Consider this review, “Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis” (JAMA, 2007):
In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality….beta carotene…, vitamin A…, and vitamin E…, singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.”
In each case, something is offsetting the benefits of ROS protection, yet these interventions have nothing in common but ROS protection itself. Stranger still, that something seems to result in the accumulation of ROS damage. But how can reducing the rate of damage fail to reduce the accumulation of damage?
There’s a relevant mathematical truism:
The bad news:
Antioxidants down-regulate autophagy (damn.)
Autophagy removes cell components — including ROS-damaged proteins and organelles — by engulfing and digesting them, producing wastes and recycled nutrients. It’s ongoing, tightly regulated, and as I discussed in “Autophagy: Why you should eat yourself”. it’s essential to life and health,
Upregulating autophagy has metabolic costs (burns
scarce calories) but has extraordinarily wide-ranging benefits. Interventions that extend healthy lifespan in animal models include calorie restriction, resveratrol, spermidine, and rapamycin, and in each operates, at least in part, through autophagy. Upregulating autophagy has positive effects in models of several specific neurodegenerative diseases, too, as I discussed in “Trehalose, autophagy, and brain repair”.
Interventions that increase production of ROS induce increased autophagy in response. As one might expect, antioxidants that reduce ROS have the opposite effect, because they reduce this inducer. There are, however, other inducers that don’t work by increasing ROS, including rapamycin and the inexpensive wonder-sugar, trehalose.
The surprising, nasty part of this story is reported in a big new paper, “Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease” (in Human Molecular Genetics, 1 September 2010). The paper has a lot of content, but in outline:
All tested antioxidants blocked autophagy induction, and all autophagy inducers were subject to being blocked. This included rapamycin and trehalose, which have nothing to do with oxidation and ROS levels, and it includes calorie restriction, too.
With caveats regarding the antioxidant doses used and the limitations of both in-vitro experiments and animal models, it seems that:
- Life-extending interventions induce autophagy.
- Strong antioxidant interventions block this effect.
In short: Slowing damage interferes with repairing damage.
This result suggests lines of research, but perhaps also directions for prudent modification of (still) popular antioxidant supplementation regimens.
Levels of antioxidants
One response is to give more credence to the negative results of antioxidant trials, because evidence for a mechanism always reinforces evidence for a result, and in this instance, the nature of the mechanism also suggests that the negative results can be generalized. This shift in the balance of the evidence tends to discourage antioxidant consumption, at the margin.
But which antioxidants, and to what extent? Although “antioxidants” may share a name, their effects differ, as do people, their aims, and their states of health. Vitamin E is not interchangeable with cocoa powder (in fact, nothing is interchangeable with cocoa powder…[slurp, return cup to table]…). Context matters, too: for example, antioxidants can have a strong positive effect on the immediate, postprandial response of the vascular system when consumed with a meal.
Timing of antioxidants
A second, compatible, direction of response might be to try shift the balance of cost and benefit associated with dietary antioxidants.
The key is that a brief interval with intensified autophagy could potentially induce a lot of repair, while forgoing supplementary antioxidants during that interval would sacrifice at most a small increment of benefit (a fraction of whatever the cumulative benefit might be).
In other words, sometimes remove the blocking agent.
How much good might upregulated autophagy do, and how quickly? Research noted in this review — “Towards an Understanding of the Anti-Aging Mechanism of Caloric Restriction” [pdf] (in Current Aging Science, 2008) — suggests surprising potential:
Recent data show that the acute stimulation of autophagy by the injection of an antilipolytic* drug can rescue older liver cells [in rats fasted for a day] from the age-related accumulation of oxidative damage of mtDNA in less than 6 hours [as indicated by levels of the marker 8-hydroxy-2-deoxyguanosine]
A strong stimulus evidently changes not just the rate of autophagy, but also the targets.
[*Addendum: Antilipolytics (for example, Acipimox high-dose niacin) inhibit fat metabolism.]
Research in autophagy is exploding. I’ve seldom explored a literature where so many of the important papers are less than a year old.
What I’ve written here is just a sample of some of the recent information, together with a few ideas about what some new information may mean for an old puzzle and some practical questions. I’m sure that there are further insights (and corrections) that can be extracted from the literature in place today, and I look forward to seeing that literature itself become half-obsolete next year.
Meanwhile, please don’t inhibit autophagy in your cells (at least not all the time), and consider giving them a healthful autophagy-inducing kick from time to time. The current state-of-the-art advice (Nature Cell Biology, September 2010) is basically simple: Fast.