{"id":59,"date":"2013-01-21T13:56:12","date_gmt":"2013-01-21T13:56:12","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=59"},"modified":"2013-01-25T03:24:26","modified_gmt":"2013-01-25T03:24:26","slug":"putting-the-brakes-on-cell-suicide","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2013\/01\/21\/putting-the-brakes-on-cell-suicide\/","title":{"rendered":"Putting the brakes on cell suicide"},"content":{"rendered":"

An eminent Russian biochemist has been working fifteen years to get the cell\u2019s most active anti-oxidant into the mitochondria, which is the locus of its action. Called \u201cSkQ\u201d for short, his designer drug administered in food, has been shown to make mice live longer; and topically it can induce regression of eye diseases in rodents, dogs and horses. While the long process of US FDA review has just begun, an eye drop containing SkQ has been approved for sale in Russia, and can now be purchased in Moscow drug stores.
\nBiochemical background: Ubiquinol in Mitochondria<\/strong><\/p>\n

Mitochondria are \u201corganelles\u201d, hundreds of independent energy factories floating within the cells of all higher life forms. Sugar is \u201cburned\u201d in the mitochondria, and the energy generated is stashed as molecules of ATP, which act like a battery that the rest of the cell can use. Muscle and nerve cells are large consumers of energy, and their function can be limited when mitochondria in aging cells begin to wane. Mitochondria have another role as well: they serve as executioners for diseased or damaged cells. It is the mitochondria that emit peroxides, which trigger a cascade of signals, culminating in cell suicide, or apoptosis<\/i>. (This story is told colorfully and creatively in a book I highly recommend, called Power, Sex and Suicide<\/a>\u00a0by Nick Lane.)<\/p>\n

Ubiquinone<\/i> was named as the enzyme that is \u201cfound everywhere\u201d. Every cell needs energy, and every cell relies on mitochondria to supply that energy, and every mitochondrion uses ubiquinone, both to create the energetic molecules of ATP that are exported for use in the cell\u2019s primary functions, and also to clean up the mitochondria\u2019s effluent of peroxides. Peroxides are an example of reactive oxygen species\u00a0<\/em>(ROS). ROS are toxic waste that corrodes the body\u2019s delicate chemistry. At higher concentrations, peroxides constitute also a distress signal which can trigger cell suicide and even export a suicide message to neighboring cells.<\/p>\n

As we age, we have less ubiquinone and there are dire consequences: less energy in our muscles and nerves; more toxic waste that damages and poisons more delicate chemicals; and over-active cell suicide that destroys healthy cells in our muscles and brains. We lose strength, sensitivity and mental acuity. Ubiquinone is sold as CoQ10, a nutritional supplement that some people take for heart health and oft-imputed anti-aging benefits. But no animal study has ever succeeded in extending life span with CoQ10. Perhaps its value is limited by bioavailability. Only a small portion of ingested CoQ10 makes its way from the stomach into the bloodstream, and a much tinier portion actually reaches the mitochondria where it is needed. This is the issue that Skulachev has addressed in such an innovative way with his molecule, which his friends and students have affectionately dubbed SkQ.<\/p>\n

 <\/p>\n

The molecule and how it works<\/strong><\/p>\n

Skuklachev\u2019s molecule is designed like a tugboat pulling a barge on a chain. The barge on the left is a molecule like ubiquinone. The 10-carbon chain is a simple hydrocarbon. And the tugboat on the right consists of a positively charged phosphorus atom, surrounded by ligand residues that delocalize and shield the charge. This works because mitochondria, in nature\u2019s design, are the only parts of a cell to carry a consistent electrical charge. They are continuously pumping protons out through their membranes, maintaining a negative electrical potential within the mitochondria.<\/p>\n

\"SkQ-structure\"<\/a><\/p>\n

The electrostatic attraction is a powerful lure, drawing the positively-charged tugboat into the mitochondria, and dragging the barge in behind. The effect is to concentrate SkQ a million-fold inside, compared to outside the mitochondria. This means that very tiny amounts can be effective antioxidants. SkQ is a very practical drug, inexpensive and non-toxic because it is administered in tiny doses.<\/p>\n

Curiously, the \u201cbarge\u201d on the left is not the version of CoQ that is used by mammals, but the plant version, called plastoquinone, which is an even more effective anti-oxidant. After comparing plastoquinone to ubiquinone in animal experiments, Skulachev switched to plastoquinone several years ago.<\/p>\n

 <\/p>\n

Anti-oxidant or signal molecule?<\/strong><\/p>\n

Readers of this column must be aware that I have been skeptical about anti-oxidants<\/a> for life extension. It appears that SkQ may be an exception because it is so precisely targeted to mitochondria. There is some precedent for the exception, in that genetic interventions that are targeted to the mitochondria have also been found to extend life span in mice. This study<\/a>\u00a0arranges for extra copies of the anti-oxidant called catalase<\/i> in the mitochondria only. Perhaps the reason for the exception is that to the mitochondria, peroxides not only cause molecular damage, but also can signal cell suicide. This is the theory that Skulachev has promoted<\/a>.<\/p>\n

He should know. In earlier days, Skulachev was responsible for elucidating the electrochemistry of mitochondria in relation to energy generation and programmed cell death.<\/p>\n

 <\/p>\n

Life extension in animals<\/strong><\/p>\n

Since 2007, Skulachev\u2019s lab at Moscow State University has been publishing studies which demonstrate life extension, first in flies and other invertebrates<\/a>\u00a0then in a variety of different rodents<\/a>. SkQ has also been shown to delay all the common diseases of aging<\/a> in rats. The effect on life span is easily discerned, and is large under some circumstances:<\/p>\n

\"SkQ-life-extension\"<\/a><\/p>\n

Administered as eye drops, the effect has been more dramatic. Rabbits have been cured of glaucoma. Macular degeneration has regressed<\/a> in horses and dogs.\u00a0\u00a0Experimenting on himself, Skulachev reports that his age-related presbyopia has regressed to the point where he can see without glasses for the first time in many years.<\/p>\n

 <\/p>\n

Present and future<\/strong><\/p>\n

SkQ has cleared the Russian equivalent of FDA approval. Clinical trials have begun for SkQ, and preliminary results indicate that 80% of people who were given the drops for cataracts experience an improvement in visual acuity within half a year (unpublished<\/a>). \u00a0As of last summer, SkQ eye drops have become available for sale in Moscow and environs through a partnership with a company named Mitotech<\/a>, under the brand name B\u0438\u0437\u043e\u043c\u0438\u0442\u0438\u043d<\/a>, or Visomitin in a more familiar script. \u00a0Sales are brisk because Skuklachev is something of a legend in his own country. There is no present timetable for marketing Visomitin in America.<\/p>\n","protected":false},"excerpt":{"rendered":"

An eminent Russian biochemist has been working fifteen years to get the cell\u2019s most active anti-oxidant into the mitochondria, which is the locus of its action. Called \u201cSkQ\u201d for short, his designer drug administered in food, has been shown to make mice live longer; and topically it can induce regression of eye diseases in rodents, … Read more<\/a><\/p>\n","protected":false},"author":65,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_post_was_ever_published":false},"categories":[1],"tags":[],"class_list":["post-59","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"yoast_head":"\nPutting the brakes on cell suicide - Josh Mitteldorf<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2013\/01\/21\/putting-the-brakes-on-cell-suicide\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Putting the brakes on cell suicide\" \/>\n<meta property=\"og:description\" content=\"An eminent Russian biochemist has been working fifteen years to get the cell\u2019s most active anti-oxidant into the mitochondria, which is the locus of its action. 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http:\/\/mathforum.org\/~josh","sameAs":["http:\/\/AgingAdvice.org"],"url":"https:\/\/scienceblog.com\/joshmitteldorf\/author\/joshmitteldorf\/"}]}},"jetpack_featured_media_url":"","jetpack_shortlink":"https:\/\/wp.me\/pgtN8h-X","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts\/59","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/users\/65"}],"replies":[{"embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/comments?post=59"}],"version-history":[{"count":0,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts\/59\/revisions"}],"wp:attachment":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/media?parent=59"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/categories?post=59"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/tags?post=59"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}