References

In this section we look at three mouse studies. In all studies removal of senescent cells increased healthy lifespan. All three studies involve wild type mice and all three studies done at Mayo Clinic, Rochester, Minn by same group.

In Baker, 2016;  treatment started at 12 months (52 weeks) at what was said to be roughly equivalent to 36 years in humans. The mice were treated with a method to remove senescent cells twice a week. The mice had extended lifespan of 24% and 27%.

In Yousefzadeh, 2018, mice started at 85 weeks of age, at what was said to be roughly equivalent to 75 years of age in humans. The mice were treated orally daily with Fisetin. Measuring the graph, the increase in post-treatment survival appears to be roughly 45% and the increase in total lifespan 12 %.

In Xu, 2018, mice started at 24-27 months (103 to 116 weeks) at what was said to be equivalent to 75-90 years in humans. Mice were treated orally with Dasatinib and Quercetin, twice a month. The post-treatment survival was increased 36% while reducing mortality hazard by 65%. The calculated increase in total lifespan was 6%.

Summary:

Study         Age Rx Start (Human)          Increase Lifespan

Baker                      36 years                              24%, 27%  

Yousefzadeh        75 years                                12%

Xu                           75-90 years                         6%

"Naturally occurring p16Inka4a-positive cells shorten healthy lifespan", Baker, 2016, Mayo clinic, Rochester, Minn.

"Fisetin is a senotherapeutic that extends health and lifespan", Yousefzadeh, 2018, Mayo clinic, Rochester, Minn.

"Senolytics Improve Physical Function and Increase Lifespan in Old Age", Xu, 2018. Mayo clinic, Rochester, Minn.

Transgenic modified wild-type mouse model of senescent cell removal

The study uses wild-type mice with a transgene which triggers apoptosis or programmed cell death with addition of a drug, "AP20187" hereafter called AP.  The cell death is only triggered in senescent cells which express p16-Ink4a, a marker also known as Cdkn2a. This is an excellent marker to track senescent cell burden and the effects on lifespan and healthspan with clearing senescent cells. 

Mice are followed from 12 months to 18 months. This is middle age mice roughly equivalent to 36 year old to 54  year old humans. Starting at 12 months, mice are treated TWICE A WEEK with AP, a procedure to remove senescent cell. At 18 months, mice were examined, with focus on adipose tissue, kidney and heart, to determine effect of clearance of senescent cells in middle age.

Adipose tissue:

Very few senescentscells were present in 12 month old mice (36 years). 

At 18 months there was an 8-fold increase in senescent cells in adipose tissue from 0.2% of cells to 1.6% in AP treated to untreated mice. 

The senescent cells were adipocyte progenitor cells (cells which have potential of forming healthy fat cells).

Kidney tissue:

At 18 months kidneys showed glomerulosclerosis (sclerotic, fibrotic glomeruli). 

Surprisingly, the senescent cells were not located in the glomeruli but in the proximal tubules. It was thought that the senescent tubule cells resulted in over activity of angiotensin system. 

Cardiac: Heart tissue showed increase in senescent cells in untreated 18 month old mice.

Cardiac aging at the histological level is characterized by loss of ventricular cardiomyocytes due to decreased ability to replace dead cardiomyocytes. The result is hypertrophy of remaining cardiomyocytes. AP treated mice showed smaller cardiomyocytes, showing production of more new cells. 

The hearts of AP treated mice with less senescent cell burden had greater ability to resist stress or more stress tolerant, i.e. less likely to develop death from arrhythmia. 

Life-long treated mice:

Tumors: 

AP treatment had effect on tumor latency. The AP treated mice had 25% greater median lifespan than the untreated mice with cancers. The AP treatment to remove senescent cells had no effect on tumor incidence or spectrum. The effect was to increase time for tumor to kill.

Median lifespan of mice dying without tumors at autopsy range from 24% to 42% increase. 

Reduction of senescent cells increased lifespan if mice with cancers and mice without cancer.

Eyes: 

AP treatment delayed cataract formation.

Appearance:

By 22 months, AP treated mice had healthier appearance and more spontaneous activity exploratory behavior. 

Wild-type mice starting at 12 months of age were injected twice a week with AP treatment to remove senescent cells. 

"We show that ...AP treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds (27%, 24%). The clearance of senescent cells delayed tumorigenesis and attenuated deterioration of several organs without apparent side effects, including kidney, heart and fat. 

"Thus (senescent cells) that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan."

Discussion: 

"Thus, our data best fit a model in which (senescent cells) act to shorten healthy lifespan by promoting tumour progression and age-dependnet changes that functionally impair certain tissues and organs, including vital organs such as kidney and heart. This, together with the key observation that elimination of (senescent cells) is not associated with any overt detrimental effects raises the possibility that this approach may be useful to tret aspects of age-relted functional decline, age-related diseases that involve senescent cells."

This study showed senescent cells accumulate in middle age; not just old age.

Unlike later studies which began treatment in old age, this study began treatment in middle age (12 month old wild-type mice) and achieved very excellent results (27%, 24% lifespan extension).

Furthermore, this study stated their were no detrimental effects to removal senescent cells starting at 1 year old mice. 

Also of note; treatment used was twice a week.