Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM.
Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3.
Finding the Holy Grail is still a long way away but this study seems to show the possibility of living longer and healthier lives
–Aging is characterized by the accumulation of cells entering a state where they cease to divide and are less functional. These cells are in a “SENESCENT” state.
a.What is Senescence ?
-Senescence is a cellular state in which cells permanently stop dividing.
-It is mediated by two signaling pathways — the p53 pathway and the p16Ink4a–Rb pathway.
-Senescent cells also secrete a complex cocktail of factors called the senescence-associated secretory phenotype (SASP), which includes destructive enzymes (matrix metalloproteinases (break down the extracellular matrix) and signaling molecules which stimulate inflammation.
b.What we know ?
-Rodents (BubR1 progeroid mice) can be genetically engineered to express INK-ATTAC (ATTAC): in senescent cells, this allows the linkage of the active p16Ink4a pathway with an enzyme called a caspase. [In more detail: transgenic mouse model that expresses the FK506-bindingprotein–caspase 8 (FKBP–Casp8) fusion protein and green fluorescent protein (GFP) under the control of a minimal Ink4a (also known as Ink4a/Arf or Cdkn2a)]
-Activation of caspase allows induction of programmed cell death (apoptosis)
-In this study from the United States (Mayo Clinic), The authors sought to examine the effects on aging when removing senescent cells
–Genetically engineered mice expressing “ATTAC” and divided into 2 groups
–AP20187 (AP) was injected in one group to induce apoptosis of senescent cells (this was done twice a week intrabdominally over a long period [in more detail from 12 weeks of life AP was injected (0.2microg g-1 2 times a week until natural death)]
-AP20187 (AP) activates caspase which then triggers apoptosis [in more detail: AP20187 (AP) is a dimerizer that activates FKBP-fused Casp8]
-Healthspan analysis was done at 18 weeks of age
-Removing these senescent cells increased lifespan (see below), regardless of the sex or strain of mouse examined, and ameliorated a range of age-dependent, disease-related abnormalities, including kidney dysfunction and abnormalities in heart and fat tissue
-The authors observed increased activity and exploratory behavior and a decrease in the incidence of cataracts. Senescent-cell removal also delayed the onset of cancer.
a.Survival curves (median survival in days)
-males and females = 27% increase in survival
ATTAC mice treated with AP: 793 days (57 mice: n=59)
ATTAC mice not treated with AP: 624days (n=57)
-males = 23% increase in survival
ATTAC mice treated with AP: 769 days (n=22)
ATTAC mice not treated with AP: 624days (n=31)
-females = 30% increase in survival
ATTAC mice treated with AP: 838 days (n=37)
ATTAC mice not treated with AP: 647 days (n=26)
4.CONCLUSION (and Authors’ comments)
-Together, these findings suggest that the accumulation of Senescent cells (p16Ink4a-expressing) during normal ageing shortens healthspan.
-ATTAC transgene that produces the caspase seems to be expressed only in senescent cells. AP might only target ‘late senescence’ cells, which express higher levels of p16Ink4a and ATTAC.
-Effects have not been observed including declines in motor performance, muscle strength and memory.
–Senescence is a protective effect which limits induction of fibrosis. It can explain delayed wound healing and is a protective mechanism. For example, In the skin removing senescent cells has no negative effect on wound healing of cancer development…However future senescence-based therapies must take this into account.
-This therapy shows that targeting senescent cells can add years to life AND life to years.
-is an immunosuppressant used in organ transplant recipients to prevent organ rejection.
–Topical Rapamycin (Sirolimus) also extends mouse lifespan and regulates the SASP. It could be interesting to see it’s effect on skin senescence.
-Topical Rapamycin is used in the treatment of angiofibromas in Tuberous Sclerosis (mTor inhibition).
Bibliography Jesús Gil and Dominic J. Withers. Out with the old. doi:10.1038/nature16875
Article selected by Saurat JH, MD