{"id":567,"date":"2017-03-28T12:09:45","date_gmt":"2017-03-28T12:09:45","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=567"},"modified":"2017-03-28T14:09:24","modified_gmt":"2017-03-28T14:09:24","slug":"senolytics-against-aging-snapshot-of-a-fast-moving-field","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/03\/28\/senolytics-against-aging-snapshot-of-a-fast-moving-field\/","title":{"rendered":"Senolytics against Aging: Snapshot of a Fast-Moving Field"},"content":{"rendered":"

Aging at the cellular level is called \u201ccell senescence\u201d, and it contributes profoundly to whole-body aging. \u00a0The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells. \u00a0Programs in universities and pharmaceutical labs around the world are racing to develop \u201csenolytic\u201d drugs, defined as agents that can kill senescent cells with minimal harm to normal cells. <\/span><\/p>\n

Apoptosis is cell suicide, and (from the perspective of the full organism) it\u2019s the best thing that can happen to senescent cells. \u00a0The authors of <\/span>this newest Dutch study<\/span><\/a> ask how it is that senescent cells escape apoptosis. \u00a0<\/span><\/p>\n

FOXO is a protein that controls gene expression, a master transcription factor associated with aging and development. \u00a0(It is the homolog in mammals of the pivotal life extension protein first identified in worms as DAF16 in the 1990s.) \u00a0FOXO4 activiation in a cell can block apoptosis. \u00a0P53 is the most common trigger of apoptosis, the first protein biochemists usually think of in connection with apoptosis. \u00a0P53 has multiple functions in the cell nucleus, but as a trigger for apoptosis, it works through the mitochondria. \u00a0FOXO4 binds to p53 and blocks its induction of apoptosis.<\/span><\/p>\n

The treatment studied in this paper is an artificially modified FOXO4, a dummy that binds to p53 in place of regular FOXO4, but doesn\u2019t block senescence. \u00a0It has been named FOXO4-DRI, and it works by crowding out the native FOXO4.<\/span><\/p>\n

The authors note, with caution, that mice with no FOXO4 at all appear\u00a0normal; but apoptosis is an important cell function throughout the lifespan. \u00a0A cell must have \u201cgood judgment\u201d about when to eliminate itself, and that works in both directions; in older animals and people, we not only see failure of apoptosis to eliminate senescent cells, but we also see healthy muscle and nerve cells undergoing apoptosis prematurely, and we lose muscle and brain mass as a result. \u00a0Other functions of FOXO4 include DNA repair, and mice that lack FOXO4 are subject to a high burden of DNA damage.<\/span><\/p>\n

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for \u201cselectivity index – 50%\u201d) is defined by analogy to LD50 = the \u201clethal dose\u201d of a toxin, the dose at which half of all cells die. \u00a0SI50 is defined as the ratio of LD50\u2019s for normal and senescent cells. \u00a0It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die. \u00a0Authors of the current paper report SI50 about 12. \u00a0My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy. \u00a0After a standard dose is injected in humans, the cellular concentrations vary from person to person and from tissue to tissue.\u00a0<\/span><\/p>\n

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection:\"\"<\/span><\/p>\n

In other words, the vertical distance between the black and red curves is encouraging, but the horizontal distance is cause for concern. \u00a0Senolytic agent studied previously, including <\/span>dasatinib, quercetin<\/span><\/a> and <\/span>ATTAC<\/span><\/a>, did not include measurements of SI50 that we might use for comparison.<\/span><\/p>\n

 <\/p>\n

How does FOXO4-DRI perform in live mice?<\/b><\/p>\n

Authors of this study were excited in a rush to publish. \u00a0They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves. \u00a0The indicatators of rejuvenation that they do report look positive: \u00a0increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.<\/span><\/p>\n

 <\/p>\n

Comparison to Last Year\u2019s Senolytic<\/b><\/p>\n

Here\u2019s how authors of the current study characterize FOXO-DRI compared to two previously reported senolytic agents:<\/span><\/p>\n

Two classes of anti-senescence compounds have been reported so far: Quercetin\/Dasatinib, either alone or in combination [ref<\/a>], and the pan-BCL inhibitors ABT-263\/737 [ref<\/a>, ref<\/a>]. Quercetin and Dasatinib have been reported to be non-specific. We found no selectivity toward senescent IMR90 and therefore this cocktail was not explored further. ABT-263 and ABT-737 target the BCL-2\/W\/ XL family of anti-apoptotic guardians. Indeed, ABT-737 showed selectivity for senescent IMR90. However, already at low doses, it appeared to influence control cells as well. Also in a treatment regimen where both compounds were added in consecutive rounds of lower concentrations, FOXO4-DRI proved to be selective against senescence yet safe to normal cells.<\/p><\/blockquote>\n

I reviewed the Quercetin\/Dasanatib paper<\/a>\u00a0two years ago. \u00a0It was an early proof-of-principle, using medications that are already known (and FDA approved). \u00a0But the 1-2 punch is not sufficiently selective–it is toxic\u00a0to\u00a0normal cells.<\/p>\n

I missed the two papers about ABT-263 \u00a0[ref<\/a>] and ABT-737 \u00a0[ref<\/a>]. \u00a0BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis. \u00a0Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2. \u00a0These two studies published in Nature<\/em> last year, one from University of Arkansas, the other from the Weizmann Institute, both use radiation exposure to create a large population of senescent cells, and then show that the senescent cells are selectively eliminted by ABT. \u00a0The ABT-263 paper included some in vivo<\/i> results, indicating enhanced growth of blood stem cells after senescent cells have been removed. \u00a0In vivo<\/i> testing of ABT-737 was limited. \u00a0Neither group reports the selectivity index (SI50) as calculated by Keizer in the latest study; but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as FOXO-DRI.<\/p>\n

\"\"
DIS and OIS are the senescent cells; G and V are the control (normal) cells. \u00a0ABT 737 (the middle bar in each of the 4 sets) kills more than half the senescent cells, but at the cost of taking out ~20% of the healthy cells.<\/figcaption><\/figure>\n
\"\"
ABT-263 appears to be more selective than ABT-737. \u00a0Normal cells (left) are not noticeably affected at a concentration where ~70% of the senescent cells are eliminated (right).<\/figcaption><\/figure>\n

The original marker used to identify and target senescent cells by the Mayo Clinic\u2019s 2011 study<\/a> was p16Ink4a<\/sup>. \u00a0The selective elimination technique they used (in 2011) was limited to genetically modified mice, but a year ago, a new paper from Mayo Clinic<\/a> demonstrated a similar procedure for ordinary, non-GMO mice. \u00a0Twice weekly injections of an antibody that induced apoptosis in cells that expressed p16Ink4a<\/sup>\u00a0extended lifespan of the mice by 25% – 30% compared to controls, comparable to the results in the 2011 paper. \u00a0Caveat: the control mice received sham injections that shortened their lifespans.<\/p>\n

 <\/p>\n

The Bottom Line<\/b><\/p>\n

The idea of removing senescent cells has a lot of appeal. \u00a0Not only does it enjoy broad empirical support in mammals; it also pulls together several ideas about the origin of aging:<\/p>\n