The Encyclopedia of Natural Medicine, 3rd Ed.

Alcohol Dependence

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• Psychological/social signs of excessive alcohol consumption: depression, loss of friends, arrest for driving while intoxicated, drinking before breakfast, frequent accidents, unexplained work absences

• Alcohol dependence as manifested when alcohol is withdrawn: delirium tremens, convulsions, hallucinations

• Alcoholic binges, benders (48 hours or more of continuous drinking associated with failure to meet usual obligations), or blackouts

• Physical signs of excessive alcohol consumption: alcohol odor on breath, flushed face, tremor, unexplained bruises

Alcohol dependence—or, as it was formerly known, alcoholism or alcohol-use disorder—is a disabling addictive disorder characterized by alcohol consumption that exceeds acceptable cultural limits or injures health or social relationships. Estimates are that in the United States, 12.5% of the population will have a problem with alcohol dependence at some point during their lifetime, while 3.8% have had a problem with alcohol dependence in the last twelve months.1

Alcohol dependence is significantly more prevalent among men, whites, Native Americans, younger adults, unmarried adults, and those with lower incomes. Alcohol dependence is one of the most serious health problems facing society today.1 The total number of Americans affected, either directly or indirectly, is much greater when one considers disruption of family life, automobile accidents, crime, decreased productivity, and mental and physical illness. With more than 100,000 deaths annually attributed to alcohol misuse, alcohol-related problems are a considerable cause of mortality.2

Consequences of Alcoholism

Increased mortality

• 10-year decrease in life expectancy

• Double the usual death rate in men, triple in women

• Six times greater suicide rate

• Major factor in the four leading causes of death in men between the ages of 25 and 44: accidents, homicides, suicides, cirrhosis

Health effects

• Metabolic damage to every cell

• Intoxication

• Abstinence and withdrawal syndromes

• Nutritional diseases

• Brain degeneration

• Psychiatric disorders

• Esophagitis, gastritis, ulcer

• Increased cancer of mouth, pharynx, larynx, esophagus

• Pancreatitis

• Liver fatty degeneration and cirrhosis

• Heart disease

• Hypertension

• Angina

• Hypoglycemia

• Decreased protein synthesis

• Increased serum and liver triglycerides

• Decreased serum testosterone

• Muscle wasting

• Osteoporosis

• Acne rosacea

• Psoriasis

• Fetal alcohol syndrome

Causes

The cause of alcohol dependence remains obscure. It represents a multifactorial condition with genetic, physiological, psychological, and social factors, all of which seem to be equally important. Serious drinking often starts in younger people: approximately 35% of alcoholics develop their first symptoms between 15 and 19 years of age, and more than 80% develop their first symptoms before age 30.3

Although alcohol dependence is most common in men, the incidence has been increasing in women: the female-to-male ratio for alcohol dependence has tapered to 1:2.1,2 Women generally seem to develop disease at a lower quantity of intake than men do. This may be partially due to women’s lower body weight and may also be related to increased gut permeability to endotoxins.4

Research indicates that genetic factors may be most important.5 The finding of a genetic marker for alcohol dependence could result in the diagnosis of the disease in its initial and most reversible stage. Some case-control studies suggest that non-gender-based gene polymorphisms encoding cytokines and other immune modulators may play a role in the predisposition to alcohol dependence. The gene patterns associated with risk reveal that antibody-mediated mechanisms could play a role in disease pathogenesis.4 The genetic basis of alcohol dependence has also been supported by the following:

• Genealogical studies show that alcohol dependence is a family condition.

• The biological children of alcoholics who have been raised by adoptive parents demonstrate a continued higher risk of alcohol dependence.

• Twin studies show differences in alcohol dependence rates between identical and fraternal twins.

• Alcohol dependence has an association with genetic markers for color vision, nonsecretor ABH, HLA-B13, and low platelet monoamine oxidase (MAO).

• Biochemical studies show the importance of alcohol dehydrogenase polymorphism in racial susceptibility to alcohol dependence.5

Although a biological marker would be useful, it may not be ultimately necessary, as an individual’s family history can suggest when it may be helpful to implement a relatively innocuous primary prevention program.

Signs of Alcohol Intoxication

The signs of alcoholic intoxication are typical of a central nervous system depressant: drowsiness, errors of commission, disinhibition, and disturbed body movements. In cases of alcohol dependence, withdrawal symptoms usually occur one to three days after the last drink. They typically range from anxiety and tremors to mental confusion, increased sensitivy to sensory stimulation, visual hallucinations, excessive sweating, dehydration, electrolyte disturbances, seizures, and cardiovascular abnormalities.

Metabolic Effects of Alcohol and Alcohol Dependence

Alcohol Metabolism

The primary metabolic processes that regulate the rate of alcohol breakdown in normal individuals are:6

• The rate of alcohol absorption from the intestines

• The concentration and activity of the liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)

• The ratio of active niacin to inactive niacin within liver cells.

It is generally accepted that the availability and regeneration of active niacin are the dominant factors affecting the rate at which alcohol is broken down.7 Alcohol is converted to acetaldehyde by the liver enzyme ADH, with active niacin as a necessary cofactor. Acetaldehyde is believed to be responsible both for many of the harmful effects of alcohol consumption and for the addictive process itself. Normally acetaldehyde is converted by another liver enzyme (ALDH) to either energy or long-chain fatty acids.6 But higher than normal blood aldehyde levels have been found in alcoholics and their relatives after alcohol consumption, suggesting either increased ADH activity or depressed ALDH activity in people susceptible to alcohol dependence.7

Fatty Liver

All active alcoholics display fatty infiltration of the liver, with the severity roughly proportional to the duration and degree of alcohol abuse. Even moderate doses of alcohol may produce both acute and chronic fatty liver infiltrates. The development of fatty liver is due to the following:6,8

• Increased fatty acid manufacture stimulated by alcohol

• Diminished triglyceride utilization

• Impaired ability to carry fatty acids away from the liver

• Direct damage to cell structures by free radicals produced by alcohol metabolism

• The high-fat diet of the alcoholic (as is typical of the average American diet)

Leptin is a peptide hormone involved in the regulation of appetite and energy metabolism. It is most likely directly related to liver pathology in alcoholics. High levels of leptin are known to contribute to fatty infiltration of the liver and other types of liver damage.9 Research has demonstrated increased circulating leptin levels in a dose-dependent manner in chronic alcohol dependence, regardless of nutritional status.10

Hypoglycemia

Alcohol consumption often results in reactive hypoglycemia, in which a rapid increase in blood glucose levels is followed by a subsequent drop. The drop in blood glucose produces a craving for food, particularly foods that quickly elevate blood glucose, such as sugar and more alcohol. Increased sugar consumption aggravates the reactive hypoglycemia, particularly in the presence of alcohol. Hypoglycemia aggravates the mental and emotional problems of the alcoholic, producing such symptoms as sweating, tremor, anxiety, hunger, dizziness, headache, visual disturbance, decreased mental acuity, confusion, and depression.

Therapeutic Considerations

Nutrition is a primary focus in alcohol dependence. Although many of the nutritional problems of alcoholics relate directly to the effects of alcohol, a major contributing factor is that alcoholics tend not to eat, instead substituting alcohol for food. As a result, the alcoholic has to deal not only with nutritional deficiencies caused by excessive alcohol consumption but also with deficiencies due to inadequate intake.

Zinc

One of the key nutrients involved in the metabolic detoxification of alcohol is zinc, as both ADH and ALDH are zinc-dependent enzymes, with the latter being more sensitive to deficiency.11 Both acute and chronic alcohol consumption result in zinc deficiency.11,12 Several factors contribute to the development of zinc deficiency in alcoholics:

• Decreased dietary intake

• Decreased absorption

• Increased urinary excretion

Low serum zinc levels are associated with impaired alcohol metabolism, a predisposition to cirrhosis, impaired testicular function, and other complications of alcohol abuse.11,13 Zinc supplementation, particularly when combined with ascorbic acid, greatly increases alcohol detoxification and survival in rats.14

Vitamin A

Vitamin A deficiency is also common in alcoholics and appears to work synergistically with zinc deficiency to produce the major complications of alcohol dependence.8,13 The mechanism has been hypothesized as follows: reduced intestinal absorption of zinc and vitamin A (alcohol damages the intestines), in conjunction with impaired liver function (reduced extraction of zinc, mobilization of retinol binding protein [RBP], and storage of vitamin A), results in reduced blood levels of zinc, vitamin A, RBP, and transport proteins, as well as a shift to nonprotein ligands. These conditions cause the tissues to have reduced concentrations of zinc and vitamin A, abnormal enzyme activities and glycoprotein synthesis, and impaired DNA/RNA metabolism; they also cause the kidneys to increasingly lose zinc. These metabolic abnormalities then lead to the common disorders of alcohol dependence:

• Night blindness

• Skin disorders

• Cirrhosis of the liver

• Slow skin healing

• Decreased testicular function

• Impaired immune function

Vitamin A supplementation inhibits alcohol consumption in female rats (though this effect is inhibited by testosterone administration and removal of the ovaries).15,16

Vitamin A supplementation in the alcoholic has improved night blindness and sexual function.8 However, great care must be employed in recommending vitamin A supplementation, as a liver damaged by excessive alcohol consumption significantly loses its ability to store vitamin A. As a result, the alcoholic is at great risk for developing vitamin A toxicity when the vitamin is supplemented at dosages above 5,000 IU per day.

Antioxidants

Alcohol consumption increases the formation of damaged fats (lipid peroxides) in both the liver and the blood. Matters are made even worse by the fact that alcoholics are typically deficient in key antioxidant nutrients, particularly vitamin E, selenium, and vitamin C, that protect against lipid peroxide formation.17,18 There is a significant link between serum lipid peroxide levels and liver damage, as shown by an elevation of the liver enzyme serum glutamate oxaloacetate transaminase (SGOT) in the blood.19 Antioxidant administration, either before or simultaneously with alcohol intake, inhibits lipoperoxide formation and prevents fatty infiltration of the liver.20 Effective antioxidants include vitamins C and E, zinc, selenium, and cysteine (in the form of N-acetylcysteine or whey protein powder).

Carnitine

The usual nutritional compounds that support liver function, such as choline, niacin, and cysteine, appear to have little value in improving liver function in the alcoholic.21,22 In contrast, carnitine significantly inhibits alcohol-induced fatty liver disease. It has been suggested that chronic alcohol consumption results in either a reduced manufacture of carnitine or an increased need.23,24 Carnitine is normally manufactured in sufficient quantities by the body. It serves a critical role in the transport of fatty acids into the mitochondria, the energy-producing structures of the cells. Supplemental carnitine improves liver function in alcoholics; it also reduces serum triglycerides and SGOT levels while elevating HDL cholesterol.24

Amino Acids

Blood levels of the various amino acids (building blocks of protein molecules) are imbalanced in alcoholics.2527 Since the liver is the primary site for amino acid metabolism, it is not surprising that alcoholics develop abnormal amino acid patterns. Correction of this disturbance greatly aids the alcoholic, especially when there are signs or symptoms of cirrhosis or depression.28 Although there are some characteristic amino acid abnormalities in alcoholics, an individual approach is indicated to address differences in nutritional status, biochemistry, and the amount of liver damage. Correction of the imbalances probably requires seeing a nutritionally oriented physician for proper analysis and treatment. That said, the branched-chain amino acids—valine, isoleucine, and leucine—can be of significant benefit for an alcoholic with cirrhosis.28

One of the typical findings in alcoholics is a very low level of tryptophan, the amino acid that is converted to serotonin. Low serotonin levels are a hallmark feature of depression. The recommendations in the chapter “Depression” are definitely appropriate to aid in recovery, especially using 5-hydroxytryptophan (5-HTP) to raise brain serotonin levels.

When there is severe alcohol-induced liver damage, the liver will be unable to convert the amino acid methionine to S-adenosyl-methionine (SAM-e), a valuable compound in normal physiology. Supplementation with SAM-e is required.29

For the alcoholic with severe liver damage, it may be necessary to lighten the load on the liver by temporarily eating a low-protein diet and supplementing the diet with free-form amino acids according to the recommendations of a physician.

Vitamin C

Vitamin C deficiency is common in alcohol-related disease—in one study, a deficiency of vitamin C was found in 91% of patients.30 Supplemental vitamin C helped ameliorate the effects of acute and chronic alcohol toxicity in experimental studies involving humans and guinea pigs, two species unable to synthesize their own vitamin C.14,31 There is a direct correlation between levels of vitamin C in leukocytes (a good index of the body’s actual vitamin C status), the rate of alcohol clearance from the blood, and the activity of the liver enzymes responsible for clearing alcohol.13 In other words, the higher the vitamin C, the better able the liver is able to clear alcohol.

Selenium

Blood selenium levels are lower in patients with alcohol dependence.18 Low selenium status contributes to depressed mood, whereas high dietary or supplementary selenium has been shown to improve mood.32 Research has consistently reported that low selenium status is associated with a significantly increased incidence of depression, anxiety, confusion, and hostility.18 Furthermore, when alcohol dependence and depression occur together in an individual, there is an increased risk for suicide.33 Given the frequency of low selenium status in alcoholics and the relationship between selenium levels and depression, selenium supplementation is warranted.

B Vitamins

Alcoholics are classically deficient in most of the B vitamins.1,8,30 These deficiencies result from various mechanisms:

• Low dietary intake

• Deactivation of the active form

• Impaired conversion to the active form

• Impaired absorption

• Decreased storage capacity

Alcohol diminishes thiamine (vitamin B1) absorption in the intestine and reduces liver thiamine storage. It also decreases the formation of thiamine into its most active form, and this effect may also contribute to the development of functional thiamine deficiency.34 A thiamine deficiency is both the most common (55% in one study)30 and the most serious of the B vitamin deficiencies, since a deficiency causes the clinical conditions beriberi and Wernicke-Korsakoff syndrome. In addition, evidence indicates that a thiamine deficiency results in greater intake of alcohol, suggesting that thiamine deficiency is a predisposing factor for alcohol dependence.35 It should be noted that once present, Wernicke-Korsakoff syndrome is unresponsive to oral doses of thiamine, so rapid replacement of depleted brain thiamine levels by repeated intravenous therapy is required.36

A functional vitamin B6 (pyridoxine) deficiency is also common in alcoholics, due not so much to inadequate intake as to impaired conversion to its active form, pyridoxal-5-phosphate, and enhanced degradation.37 In addition to inhibiting conversion to more active forms, alcohol decreases the absorption and utilization by the liver and increases the urinary excretion of many B vitamins, especially folic acid.38

Magnesium

Magnesium deficiency is very common in alcoholics. In fact, one study found deficiency in as many as 60% of alcoholics and a strong link to delirium tremens (a state of confusion and trembling during alcohol withdrawal).39 It is thought to be the major reason for the increased cardiovascular disease noted in alcoholics. This deficiency is due primarily to a reduced magnesium intake coupled with alcohol-induced excessive excretion of magnesium by the kidneys, which continues during withdrawal despite low serum magnesium levels. Alcoholic cardiomyopathy, often associated with thiamine deficiency, may instead be due to a magnesium deficiency.

Essential Fatty Acids

Alcohol has been shown to interfere with essential fatty acid (EFA) metabolism and may produce symptoms of essential fatty acid deficiency if consumed in excess.40 In a five-year study, alcohol-consuming rhesus monkeys developed alcoholic amblyopia, a rare neurological disorder characterized by blurred vision, diminished retinal function, and a significant reduction in visual acuity; biopsies showed that the omega-3 fatty acid DHA level in the monkeys’ brains and retinas had decreased significantly compared with that in controls.41 Given the importance of long-chain fatty acids to brain function, it may be useful to supplement EPA + DHA in alcoholics.

Glutamine

Supplementation of the amino acid glutamine (1 g per day) has been shown to reduce voluntary alcohol consumption in uncontrolled human studies and experimental animal studies.4244 Although this research occurred more than 50 years ago, there has never been any follow-up to these preliminary studies. This is unfortunate, as the results were promising and showed the supplement to be safe and relatively inexpensive.

Psychosocial Aspects

Psychological and social measures are critical in the treatment of alcohol dependence, as it can be a chronic, progressive, and potentially fatal disease.1 Social support for both the alcoholic and his or her family is important, and treatment success is often proportional to the involvement of Alcoholics Anonymous (AA), counselors, and other social agencies. Because most physicians have not had adequate training or experience in handling the psychosocial aspects of this problem, it is important to establish a close working relationship with an experienced counselor and AA. Al-Anon and Ala-Teen are useful resources for family members. Successful initiation of treatment requires the following:

• The alcoholic’s agreement that he or she has an alcohol problem

• Education about the physical and psychosocial effects of alcohol dependence

• Immediate involvement in a treatment program

Successful programs (such as AA) usually include strict control of drinking, strongly supported by family, friends, and peers. Although strict abstinence may not be absolutely necessary, at this time it appears the safest and most effective choice.1

Depression

Depression is common in alcoholics and is known to lead to their high suicide rate. In some cases depressed individuals become alcoholic (primary depressives), while others become alcoholic first and later develop a depressive condition in the context of their alcohol dependence (secondary depressives). Alterations in the metabolism of brain chemicals such as serotonin and the availability of its precursor, tryptophan, have been implicated in some forms of depression, while other forms have been linked to alterations in catecholamine metabolism and tyrosine availability.

As mentioned above, alcoholics have severely depleted levels of tryptophan, which may explain both the depression and the sleep disturbances common in alcohol dependence, since brain serotonin levels depend on circulating tryptophan levels.45 Alcohol impairs tryptophan transport into the brain and increases the enzyme that breaks down tryptophan.25 In one study, five of six chronic alcoholics had no detectable plasma tryptophan on withdrawal.26 The tryptophan levels returned to normal after six days of treatment and abstinence.

Another factor influencing tryptophan uptake into the brain is competition from amino acids that share the same transport mechanism, especially tyrosine and phenylalanine, which are elevated in malnourished alcoholics. Alcoholics have significantly depressed ratios of tryptophan to these amino acids when compared with normal controls, with depressed alcoholics having the lowest ratios.26,46

Following the recommendations in the chapter “Depression” is definitely appropriate to aid in recovery, especially using 5-hydroxytryptophan (5-HTP) to raise brain serotonin levels.

Intestinal Flora

The intestinal microflora is severely deranged in alcoholics.47 Colonization of the small intestine by bacteria that produce endotoxins may lead to malabsorption of fats, carbohydrates, protein, folic acid, and vitamin B12. This mechanism is probably the cause of the abnormalities of the small intestine commonly found in alcoholics. Alcohol ingestion also increases intestinal permeability to endotoxins and large particles that can activate the immune system adversely.48

Exercise

The involvement of the alcoholic patient in an individually tailored fitness program has been shown to improve the likelihood of maintaining abstinence.49 Research has shown that regular exercise is effective in alleviating anxiety and depression and enables individuals to respond better to stress. Improved fitness may allow more effective responses to emotional upset, thereby reducing the likelihood of resorting to alcohol when the patient is involved in conflict.

Botanical Medicines

Kudzu

Kudzu (Pueraria lobata) was one of the earliest medicinal plants used in traditional Chinese medicine. It has many profound pharmacological actions, including helping prevent alcohol abuse.50 Two of its isoflavones, daidzin and daidzein, account for this effect.51 These compounds are also found in soy foods. Rodent studies have been impressive, but in human studies the results have been mixed. In one study, kudzu treatment resulted in significant reduction in the number of beers consumed: the time to consume each beer increased, with the number of sips increasing and the volume of each sip decreasing.52However, in a double-blind trial, kudzu root extract (1.2 g twice per day) produced no statistically significance difference in craving and sobriety scores compared with the placebo group.53 It may be that kudzu reduces alcohol intake without significantly affecting cravings.

Milk Thistle

The flavonoid complex of milk thistle (Silybum marianum, or silymarin) appears to be useful for the alcoholic, especially when there is considerable liver involvement or cirrhosis. Silymarin has been shown to be effective in the treatment of the full spectrum of alcohol-related liver disease, from relatively mild to serious cirrhosis. Perhaps the most significant benefit is extending the life span of these patients. In one study 87 cirrhotics (46 with alcoholic cirrhosis) received silymarin, while 83 cirrhotics (45 with alcoholic cirrhosis) received a placebo.54 The average observation period was 41 months. In the silymarin group, there were 24 deaths with 18 related to liver disease, while in the control group there were 37 deaths with 31 related to liver disease. The four-year survival rate was 58% in the silymarin group, compared with 39% in the controls.

Silymarin can also improve immune function in patients with cirrhosis.55 Whether this effect is involved in the liver protective action or a result of improved liver function has yet to be determined.

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QUICK REVIEW

• Genetic factors play a big role in the development of alcohol dependence.

• All active alcoholics display signs of injury to the liver.

• Hypoglycemia aggravates the mental and emotional problems of the alcoholic.

• Zinc is one of the key nutrients involved in the breakdown of alcohol.

• Vitamin A deficiency is also common in alcoholics and appears to work together with zinc deficiency to produce the major complications of alcohol dependence.

• Antioxidants taken either prior to or along with alcohol inhibit free radical damage and the development of a fatty liver.

• Carnitine inhibits alcohol-induced fatty liver.

• There is a direct link between the level of vitamin C in white blood cells and the rate of clearance of alcohol from the blood.

• Thiamine (vitamin B1) deficiency is both the most common and the most serious of the B vitamin deficiencies in the alcoholic.

• Low magnesium levels are present in as many as 60% of alcoholics and are linked to delirium tremens.

• Glutamine supplementation (1 g per day) has been shown to reduce voluntary alcohol consumption in uncontrolled human studies.

• Kudzu, an ancient Chinese herbal medicine, has shown good results in reducing alcohol consumption in human studies.

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TREATMENT SUMMARY

Alcohol dependence is a difficult condition to treat. Although many therapeutic regimens have been attempted, there has been little documented long-term success, except for Alcoholics Anonymous (and even the overall success of this program is highly controversial). All alcoholics, at whatever stage, benefit the most from simultaneous counseling, lifestyle, and nutrition-oriented approaches.

Lifestyle

Follow the recommendations given in the chapter “A Health-Promoting Lifestyle,” as well as those in the chapter “Stress Management.” It is especially important to:

• Identify stressors

• Eliminate or reduce sources of stress

• Identify negative coping patterns and replace them with positive patterns

• Perform a relaxation/breathing exercise for a minimum of five minutes twice per day

• Manage time effectively

• Enhance your relationships through better communication

• Get regular exercise

Diet

Stabilization of blood sugar levels is critical to successful treatment. The recommendations given in the chapter “A Health-Promoting Diet” should serve as the foundation for the dietary treatment of alcohol dependence. Key dietary recommendations include elimination of all simple sugars (foods containing added sucrose, fructose, or glucose; fruit juice; dried fruit; and low-fiber fruits such as grapes and citrus fruits); limitation of processed carbohydrates (white flour, instant potatoes, white rice); and an increase in complex carbohydrates (whole grains, vegetables, beans).

Nutritional Supplements

• A high-potency multiple vitamin and mineral formula as described in the chapter “Supplementary Measures”

• Key individual nutrients:

  images Vitamin A: 2,500 to 5,000 IU per day (use beta-carotene if suffering from liver impairment)

  images Vitamin B complex: 20 times the RDI

  images Vitamin C: 1 g two times per day

  images Vitamin E: 100 to 200 IU per day

  images Magnesium (citrate or aspartate): 250 mg two times per day

  images Selenium: 200 mcg per day

  images Zinc: 30 mg per day

• Fish oils: 3,000 mg EPA + DHA per day

• One of the following:

  images Grape seed extract (>95% procyanidolic oligomers): 100 to 300 mg per day

  images Pine bark extract (>95% procyanidolic oligomers): 100 to 300 mg per day

  images Some other flavonoid-rich extract with a similar flavonoid content, super greens formula, or another plant-based antioxidant that can provide an oxygen radical absorption capacity (ORAC) of 3,000 to 6,000 units or higher per day

• Specialty supplements:

  images Probiotic (active lactobacillus and bifidobacteria cultures): a minimum of 5 billion to 10 billion colony-forming units per day

  images Carnitine: 500 mg two times per day (L-carnitine)

  images Glutamine: 1 g per day

  images If depression is an issue, 5-hydroxytryptophan: 50 to 100 mg three times per day

Botanical Medicines

• Kudzu (Pueraria lobata) root extract: 1.2 g twice per day

• Milk thistle extract (70 to 80% silymarin): 70 to 210 mg three times per day, with higher dosages if there is significant liver involvement; dosage for silymarin phytosome is 120 mg two to three times per day between meals

Other Considerations

• Establish a good working relationship with Alcoholics Anonymous or an experienced counselor who has particular expertise in working with alcoholics.

• It is important to establish a strong network of caring family, friends, and peers for support. Get involved and busy with intense, people-oriented activities. Develop better strategies to deal with stress and the challenges of life.