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
|
Gli editoriali più recenti |
|