Resveratrol inhibits tobacco-induced inflammation: Put that in your pipe and smoke it

Smoking is bad for you.

Sometimes the sheer scope of its badness takes my breath away, no pun intended: The tars damage DNA directly, and are thus carcinogenic; each puff is loaded with carbon monoxide and trillions of oxidative radicals; and the lung reacts to the smoke by releasing pro-inflammatory cytokines that cause fibrotic changes in that tissue, changes that in the long run can be every bit as lethal as cancer. We know this, yet many of us who know better still smoke: evidence not of ignorance or failed willpower but of the pernicious addictiveness of nicotine.

Smoking is bad for you.

But a protein that is positively involved in lifespan determination may also protect the body by decreasing the harmful inflammatory response to tobacco. SIRT1, one of the sirtuins, downregulates the release of pro-inflammatory cytokines by lung cells exposed to cigarette smoke — specifically, inhibitors of SIRT1 aggravate the inflammation while the now-famous natural product activator resveratrol decreases it. From Yang et al. (emphasis mine):

The Silent information regulator2 (Sir2) family of proteins (sirtuins or SIRT) which belong to class III histone/protein deacetylases, have been implicated in calorie restriction, aging and inflammation. We hypothesized that cigarette smoke-mediated pro-inflammatory cytokine release is regulated by SIRT1 by its interaction with NF-{kappa}B in the monocyte-macrophage cell line (MonoMac6) and in inflammatory cells of rat lungs. Cigarette smoke extract (CSE) exposure to MonoMac6 cells caused dose- and time-dependent decrease in SIRT1 activity and levels, that was concomitant to increased NF-{kappa}B-dependent pro-inflammatory mediators release. Similar decrements in SIRT1 were also observed in inflammatory cells in the lungs of rats exposed to cigarette smoke as well as with increased levels of several NF-{kappa}B-dependent pro-inflammatory mediators in bronchoalveolar lavage fluid and in lungs. Sirtinol, an inhibitor of SIRT1, augmented whereas resveratrol, an activator of SIRT1, inhibited CSE-mediated pro-inflammatory cytokine release. CSE-mediated inhibition of SIRT1 was associated with increased NF-{kappa}B levels. Furthermore, we showed that SIRT1 interacts with RelA/p65 subunit of NF-{kappa}B, which was disrupted by cigarette smoke, leading to increased acetylation RelA/p65 in MonoMac6 cells. Thus, our data show that SIRT1 regulates cigarette smoke-mediated pro-inflammatory mediator release via NF-{kappa}B implicating a role of SIRT1 in sustained inflammation and aging of the lungs.

The logic of the gene regulation here is a bit twisted and surprising: The drug studies indicate the direction of SIRT1’s influence: increasing sirtuin activity decreases inflammation. But — counter-intuitively for a stress response, where one expects protective proteins to be expressed at higher levels in the presence of the stressor — SIRT1 activity is downregulated by cigarette smoke. So even though SIRT1 is protective, in that it decreases the body’s harmful inflammatory response to smoke, its efficacy is diminished by the very toxins it would protect us against.

It’s yet another way in which smoking is bad — it locally accelerates the aging process.

But the sirtinol/resveratrol results give hope to the idea of using sirtuin activators (which are likely to have anti-aging effects) to address specific, clearly defined clinical issues. Comparable to the idea of using sirtuin activators to combat metabolic syndrome, one could imagine administering resveratrol or its derivatives to nicotine addicts who are having a hard time kicking the habit. It wouldn’t make smoking safe, but it would help prevent the fibrotic changes that smoking causes in the lung, so that after patients attain their goal of full abstinence, they can look forward to a healthier life — with younger lungs than they might otherwise have.

Such an approach provides another path to regulatory approval of sirtuin activators, whose off-label uses (for those patients not lucky enough to be at risk for metabolic syndrome, type II diabetes or pulmonary fibrosis) might include treatment of the long-term time-dependent deterioration of tissue function that is the major risk factor for most life-threatening diseases — i.e., aging itself.