Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1

Abstract

MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of ≈100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general.

The exceptional longevity of the naked mole‐rat may be explained by mitochondrial antioxidant defenses

“…Third, the possibility that the evolution of long lifespan proceeds through upregulation of matrix antioxidants and not by modifying sites of ROS production has profound implications for the medical domain. For instance, such a finding may foster additional interest in developing synthetic antioxidants targeted to mitochondria for the postponement of aging‐related diseases (Shabalina et al, ; Skulachev et al, ). Future studies are required at this point to investigate whether greater mitochondrial capacity to consume H 2 O 2 is a generalized trait across long‐lived species relative to their shorter‐lived counterparts, which would represent a major paradigm shift in the field of aging.…”

“…For example, the overexpression of catalase targeted to mitochondria is one of the rare genetic interventions that can extend the lifespan of vertebrates (Dai et al, ; Schriner et al, ). Similarly, synthetic antioxidants chemically targeted to mitochondria (e.g., SkQ1) can extend healthspan of wild‐type rodents (Skulachev et al, ), and both healthspan and lifespan of mtDNA mutator mice (Shabalina et al, ). Furthermore, the (genetically engineered) loss of the antioxidant and electron carrier ubiquinone results in the partial loss of mitochondrial function and shortened lifespan in a mouse model (Wang, Oxer, & Hekimi, ).…”

“…More recently, however, the mitochondrial oxidative stress hypothesis of aging has gained empirical support (Barja, ; Dai, Chiao, Marcinek, Szeto, & Rabinovitch, ; Kujoth et al, ; Kukat & Trifunovic, ; Pamplona, ; Shabalina et al, ; Trifunovic et al, ); however, this hypothesis remains controversial (Stuart et al, ), and has not yet been investigated in NMRs. This refined hypothesis stems from the fact that mitochondrial ROS are mostly released inside the mitochondrion (i.e., within the mitochondrial matrix), thereby directly exposing mitochondrial biomolecules to oxidative damage.…”

Comparative studies of mitochondrial reactive oxygen species in animal longevity: Technical pitfalls and possibilities

“…There is now ample evidence that the oxidation of renewable cytosolic macromolecules such as proteins is not directly related to longevity (Andziak, O'Connor, & Buffenstein, ; Hekimi et al, ; Lewis, Andziak, Yang, & Buffenstein, ; Stuart et al, ). Instead, the debate has now shifted to the question of whether or not oxidation of mitochondrial DNA (mtDNA), or other permanent damage to mitochondria, represents an important contribution to the process of senescence (Barja, ; Dai, Chiao, Marcinek, Szeto, & Rabinovitch, ; Kukat & Trifunovic, ; Shabalina et al, ), and if this effect could thus be modulated to extend longevity. Within this revised context, it could nonetheless be argued that the balance between the rates of H 2 O 2 formation and consumption inside the matrix is represented by H 2 O 2 efflux.…”

Sapiens Mitochondrial DNA Genome Circular Long Range Numerical Meta Structures are Highly Correlated with Cancers and Genetic Diseases mtDNA Mutations

“…Various heterogeneous genomes copies can be found in the same cell, it is heteroplasmia [7]. It would also appear that the genome of mitochondria and its mutations can play an important role in aging [8,9]. But, above all, simple mutations associated with various diseases (such as LHON) are observed, and somatic mutations are found in cells associated with various diseases such as cancers [10].…”