each cigarette smoked is estimated to shorten life by 11 minutes. Starting smoking earlier in life and smoking cigarettes higher in tar increases the risk of these diseases. The World Health Organization estimates that tobacco kills 8 million people each year as of 2019 and 100 million deaths over the course of the 20th century. Cigarettes produce an aerosol containing over 4,000 chemical compounds, including nicotine, carbon monoxide, acrolein, and oxidant substances. Over 70 of these are carcinogens. The most important chemical compounds causing cancer are those that produce DNA damage since such damage appears to be the primary underlying cause of cancer. Cunningham et al. combined the microgram weight of the compound in the smoke of one cigarette with the known genotoxic effect per microgram to identify the most carcinogenic compounds in cigarette smoke. The seven most important carcinogens in tobacco smoke are shown in the table, along with DNA alterations they cause. "Ulcerative colitis is a condition of nonsmokers in which nicotine is of therapeutic benefit." A recent review of the available scientific literature concluded that the apparent decrease in Alzheimer disease risk may be simply because smokers tend to die before reaching the age at which it normally occurs. "Differential mortality is always likely to be a problem where there is a need to investigate the effects of smoking in a disorder with very low incidence rates before age 75 years, which is the case of Alzheimer's disease", it stated, noting that smokers are only half as likely as nonsmokers to survive to the age of 80. Gateway theory A very strong argument has been made about the association between adolescent exposure to nicotine by smoking conventional cigarettes and the subsequent onset of using other dependence-producing substances. Strong, temporal, and dose-dependent associations have been reported, and a plausible biological mechanism (via rodent and human modeling) suggests that long-term changes in the neural reward system take place as a result of adolescent smoking. Adolescent smokers of conventional cigarettes have disproportionately high rates of comorbid substance use, and longitudinal studies have suggested that early adolescent smoking may be a starting point or "gateway" for substance use later in life, with this effect more likely for persons with attention deficit hyperactivity disorder (ADHD). Although factors such as genetic comorbidity, innate propensity for risk-taking, and social influences may underlie these findings, both human neuroimaging and animal studies suggest a neurobiological mechanism