**5. Aging: The role of dehydrogenases in metabolic and mitochondrial dysfunction**

102 Dehydrogenases

expectations (69).

**4.4. IEM related to fatty acid oxidation** 

employed in cases with MCAD deficiency.

four straight chain acyl coA dehydrogenases such as:

 Short chain acyl coA dehydrogenase (C4-C6 fatty acyl coAs) Medium Chain acyl coA dehydrogenase (C6-C10 fatty acyl coAs) Long Chain acyl coA dehydrogenase (C10-C14 fatty acyl coAs) Very Long Chain acyl coA dehydrogenase (C14-C20 fatty acyl coAs)

Current therapies are mostly symptomatic, directed at seizure treatment and amelioration of neurobehavioral symptoms. Antiepileptic drugs such as carbamazepine and anti-anxiety drugs may be administered in conjunction with physical and occupational therapy. Early attempts to use Vigabtrin (GABA transaminase inhibitor) did not meet the therapeutic

Fatty acids are a major source of energy in heart as well as muscle. Fatty acid oxidation (FAO) is a series of four reactions occurring in mitochondria. The first step is catalyzed by

Medium chain acyl-coA dehydrogenase (MCAD) deficiency is the most common fatty acid oxidation-related disorder (1:10000 to 1:30000 in US) which is inherited in an autosomal recessive fashion (70-72). MCAD is an enzyme that catalyzes breakdown of fatty acids for energy production during long periods of prolonged fasting. Accumulation of octanoylcarnitine with Reye-like syndrome is typical clinical manifestation of this disorder (73;74). Children can exhibit severe hypoglycemia in mild illnesses. It can also lead to sudden infant like death syndrome (75). Symptoms may appear from 2 days to 6.5 years of age, however the patient can also remain asymptomatic for long time. When left undiagnosed MCAD deficiency has a mortality of 20% and 10-15% are severely handicapped. A case study of diagnosis as late as 30 years of age is reported in literature. The 30 year old man exhibited rhabdomyolysis, muscle weakness, acute encephalopathy after exertion in cold and fasting. Urine detection of carnitine led to the diagnosis of MCAD deficiency. Point mutation at position 985 in the coding region of MCAD gene was detected. 449\_452 deletion mutation is also studied. During acute episodes, symptomatic relief to overcome hypoglycemia cerebral edema, seizures or metabolic acidosis is the main line of treatment. Avoiding long periods of fasting is the best preventive measure that can be

Short chain acyl coenzyme A dehydrogenase deficiency (SCAD) is another autosomal recessive disorder in mitochondrial fatty acid oxidation. It is characterized by increased C4 carnitine in plasma and ethylmalonic acid in urine. Clinical symptoms which appear early in life include developmental delay, hypotonia, epilepsy and behavioral disorders along with hypoglycemia and myopathy (76;77). Unlike MCAD deficiency, if neonatally screened and followed up it is found to remain asymptomatic, thus the clinical disease outcome of SCAD deficiency is questionable. Thus, need for treatment is not clear. Avoidance of fasting for longer hours with age appropriate diet is the only recommendation for prevention of primary manifestation. Annual checkup for growth, development is generally suggested.

Aging or growing old is defined as a time related loss and decline in certain morphological, anatomical and functional features of body in comparison to its previous state. Beginning as a maturation process from childhood to young adulthood, it assumes the characteristic of decline through middle and late ages. Accumulation of molecular, cellular, or organ level damage leads to higher vulnerability of disease and eventually death. There have been numerous theories and hypothesis for causes of aging but it is still under investigation and discussion. "The Free Radical Theory of aging (ROS generation), shortening of telomerase, DNA methylation and epigenetics are few main ones. Important to us is the "The Free Radical Theory of aging since it is closely associated with mitochondria, and linked DHOs (78-81).

Broadly, both genetic as well as external environmental factors can be responsible for promoting the age associated decline in functionalities (82). Oxidative stress and dietary restrictions can influence the genes externally. "Oxygen derived species", "Reactive nitrogen species" and "Reactive aldehydic species" can cause changes at cellular level ensuing damage to our natural defense mechanisms affecting repair and elimination processes in the body. In totality, irregularities in function, oxidative changes and the piled up cellular damages can lead to homoeostatic imbalance which finally result in aging as well as agerelated diseases. "The Free Radical Theory of aging" suggests generation of superoxide radical, hydrogen peroxide and hydroxyl radical as a side reaction to the electron transport chain at mitochondrial membrane (83). These free radicals can cause enzyme inactivation to different extent with different mechanisms (see **Figure 6**). Studies show that mitochondrial enzymes are resistant to hydrogen peroxide free radical but are fairly affected by hydroxyl free radical. On the other hand oxygen free radical by itself can cause significant oxidative damage with respect to inactivation of mitochondrial enzymes like NADH dehydrogenase, succinate dehydrogenase, NADH oxidase, succinate oxidase and ATPase 2.

Link between aging and various dehydrogenase enzymes is based on the energy demand of our body which involves the participation of different dehydrogenases for production of ATP at cellular level (as elaborated in the earlier section of energy metabolism). Several dehydrogenases involved in energy metabolism can exhibit altered activity or complete inactivation with aging. This can result in hampering energy production as well as accumulation of toxic metabolites in the body.
