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Study of an old Man's Profile - Galleria degli Uffizi - Firenze
Aging of the skeletal muscle and myocardium: the role of damaged mitochondria Torna agli editoriali

di
Anna Giulia Cattaneo,DBSM

Sarcopenia, associated with reduced type 2 fibres and myosin, and myocardial alterations are a major cause of morbidity and mortality at old age.
Respiratory rate is high in both districts, and critical for functional performance. The hypothesis of an oxidative damage of mitochondria, the organelles playing a central role in respiration and apoptosis, is attractive to explain at least in part some degenerative processes associated with aging, both under a merely speculative and an experimental point of view.

This Editorial is aimed to discuss experimental evidences suggesting an association between mitochondrial damage in muscular districts, both skeletal and myocardial, and aging, and their possible implications for functional impairment.

The possibility to prevent damage by dietary measures, like caloric restriction and exercise, or administration of hormones and antioxidant agents is evaluated on the basis of the existing literature.

The damaged mitochondrion

Aging seems to affect mitochondria in multiple ways: structural and functional changes have been found, and acquired genetic defects possibly due to oxidative damage of mitochondrial genome, mtDNA, have been described. The damage in itself could initiate the apoptotic process, and subsequently involve the entire cell.
In particular, mitochondria appear disrupted in their inner membrane order, and enlarged in aged myocytes. In addition to it, and in part as a consequence of it, aging mitochondria seem to be partially protected from autophagy and prone to clone themselves.
It is controversial if accumulation of deleted mtDNA is compensated by increased synthesis, and cloned expansion seems to be related to fission and fusion processes, this hypothesis being supported by experimental evidence (Kowald A. et al. (2005): Aging Cell. 4, 273-83).

Significant reduction of respiratory rate and Reactive Oxygen Species (ROS) generation followed by oxidative damage have been described during aging both in tissues and cells from animals and humans. ROS are common products of respiration, accumulating in dangerous amounts only when the efficiency of the enzymatic respiratory chain (also called OXPHOS pathway) is disrupted. In this case, activation of mitochondrial permeability transition pore (mtPTP, a preapoptotic event) and mtDNA mutations occurs.
A distinction should be done between endogenous and exogenous production by mitochondria: the endogenous one, if excessive, leads to local damage (peroxidation) of mtDNA and accumulation of lipo- and glycoperoxides into the mitochondrial membrane system. Oxidative damage of mtDNA can affect all genes, and all functional activities (e- transport, glycolysis/TCA cycle, muscle structure/function, apoptosis and stress-associated changes) can be affected by it, as proved by experimental evidences obtained in humans and in rodents.

Instead, the excessive release of ROS from damaged mitochondria, which seems to be regulated by the cytoskeleton, leads to nuclear and cellular oxidative damage.

The process of arteriosclerosis, at least in its early phase, appears to be related to oxidative damage of ROS escaped from mitochondria-rich cells into extracellular fluids.

Behavioural changes can positively affect the oxidative damage

Possible nutritional and behavioural remedies to reduce or even revert the age-associated alteration listed in the previous paragraph are constantly proposed by different groups of scientist and physicians.

Between other, dietary restriction is a well-known protective factor against aging in animals, where a significant enlargement of life span or expectancy can be obtained in this way. Markers for protein glyco- and lipoxidation of mitochondrial structures, reduced activity of a wide number of mitochondrial enzymes and coenzymes (citrate kinase, complexes I, II and III, heme-a and complex IV, coenzyme Q, alpha-tocopherol, DT-diaphorase, NADP+-isocitrate dehydrogenase between other) have been found to be higher in aging rodents fed "ad libitum". They decrease even at normal levels in animals submitted to caloric restriction.

However, the efficacy of these means in humans is not evident as in species having a much shorter life-span, and difficulties raise in permanently introducing changes of life styles in our species. In addition, it should be taken into account that elder people are exposed to the risk of unbalanced dietary intake. Mineral and vitamin deprivations (iron, zinc and biotin among others) display potential attitudes to enhance aging damages due to ROS in many districts, included mitochondria, muscles and heart, while their addiction to the diet shows protective effects.

The addition of light antioxidant agents to the diet, like the green tea has been claimed beneficial against damage, and some experimental evidences supporting this hypothesis have been produced. This protective measure could be accepted as beneficial, at least as a pleasant habit, waiting for more strong evidences of its real protective activity against ROS.

Physical exercise is another discussed and potentially useful anti-aging measure, that positively affects lower protein turnover and resting metabolic rate, decrease of muscle aerobic capacity, skeletal muscle strength, reduction of type 2 muscle fibres and myosin heavy chains IIa and IIx. . The effect of exercise seems to be a generic one, found both in young and in aged people or animals, but no clear evidences for a specific anti-aging effect have been stated. Again, introducing a reasonable amount of exercise in living habits of elder person is a potential mean for improving life quality, possibly reducing depression and restoring self-esteem. So, it should be highly recommended, in any way.

Experimental pharmacology: suggestions for an effective treatment

A complete discussion of all the anti-aging drugs proposed to restore muscle strength and protect against myocardial damage is by far over the aim of an Editorial. Only a few notes are reported here, concerning major groups of treatments potentially useful to ameliorate muscle damage in elderly.

Aging and hormones have grown in a strict binomial association from the time the word hormone has been used in a modern meaning, and is entered in the popular thinking as a number of partially not-critically proposed stereotypes. The diffused opinion that adding testosterone could restore at least in men a lost youth and strength, or the recent misuse of GH since the introduction of human molecule in large and relatively cheap amounts into the commercial world, contrast with the number of side-effects accompanying these therapies. Cautiously and seriously planned experimental protocols are needed to find new ways in restoring hormonal deficiencies associated with the loss of functionality in different districts with the necessary safety. Elderly remains a frail domain of human life, in which medical interventions should be entered with great care and strong motivations.

The same could be true for the number of molecules and drugs proposed as beneficial. Only a short selection of them can be recalled here.

Melatonin comes first of all, for its role as antioxidant agent, its relatively low or non-existent toxicity and large publicity given by media. Its efficacy and safety in humans remains however to be proved, and it seems to be desirable that a final statement should be provided, in order to avoid confusion and false expectations at the present evocated by the name itself. Experimental data concerning the effect of melatonin as antioxidant in damaged muscle mitochondria remain limited to theoretical hypothesis and have been only sporadically collected in animals.

N-acetylcysteine and aminoguanidine added to diet or drinking water seems to repair age-associated oxidative damage, even at the muscle mitochondrion level. Even in this case, studies have been limited to aged rodents.

In conclusion, during the aging process, mitochondria seem to be both a production site and a target of oxidative damage in skeletal muscle and in myocardium. A number of markers for the oxidative damage have been identified, and preventive measures proposed. Between them, moderate exercise, cautious dietary control, and addition of non-dangerous antioxidant can be regarded as protective measure that can at least ameliorate the life quality of the elder patient, if not enhance life expectancy. New drug or hormone administrations have to be carefully considered.

Anna Giulia Cattaneo, DBSM, Università dell'Insubria, Via J-H Dunant,3 - 2100 Varese

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