You can’t teach an old kidney new tricks: cellular senescence in organ transplants

Cellular senescence likely evolved as a defense against cancer: Damaged cells stop dividing, preventing cells that have sustained oncogenic mutations from proliferating and forming tumors. One down side is that the proliferative capacity of the organ goes down; another is that persistent senescent cells secrete factors that damage the extracellular matrix and contribute to age-related decline in tissue function.

Because senescent cells accumulate with age, senescence has been considered a biomarker of aging — that is to say, a measurable feature of a tissue that would allow us to calculate its “biological” or “physiological” age without necessarily knowing the chronological age of the donor. This makes abundant sense: tissues with more senescent cells would have lower proliferative capacity and higher levels of deleterious secreted factors; given two samples of the same chronological age, one could argue that the one containing more senescent cells was “older” in some meaningful way.

This idea is central to a recent paper demonstrating that senescence correlates negatively with the efficacy of a transplanted tissue. Grafts from older donors have poorer outcomes than those from younger donors, but some older tissues work just fine — what’s the difference between an old graft that works and an old graft that doesn’t? The answer, in part, is the level of expression of senescence markers: Higher expression of senescence-related genes predicts a poorer outcome in a transplant. In other words, controlling for chronological age, physiological age is a negative correlate of transplant efficacy. From McGlynn et al.:

Cellular senescence in pre-transplant renal biopsies predicts post-operative organ function

Older and marginal donors have been used to meet the shortfall in available organs for renal transplantation. Post transplant renal function and outcome from these donors is often poorer than chronologically younger donors. Some organs, however, function adequately for many years. We have hypothesised that such organs are biologically younger than poorer performing counterparts. We have tested this hypothesis in a cohort of pre-implantation human renal allograft biopsies (n=75) that have been assayed by Real Time-PCR for the expression of known markers of cellular damage and biological ageing, including CDKN2A, CDKN1A, SIRT2, and POT1. These have been investigated for any associations with traditional factors affecting transplant outcome (donor age, cold ischaemic time) and organ function post transplant (serum creatinine (SC) levels).

Linear regression analyses indicated a strong association for SC with pre transplant CDKN2A levels (p=0.001) and donor age (p=0.004) at six months post transplant. Both these markers correlated significantly with urinary protein to creatinine ratios (p=0.002 and p=0.005 respectively), an informative marker for subsequent graft dysfunction. POT1 expression also showed a significant association with this parameter (p=0.05).

Multiple linear regression analyses for CDKN2A and donor age, accounted for 24.6% (p=0.001) observed variability in SC levels at six months and 23.7% (p=0.001) at one year post transplant. These data indicate that allograft biological age is thus an important novel prognostic determinant for renal transplant outcome.

Note that the authors measured the levels of senescence-associated gene expression, rather than the number of cells in the tissue that were senescent. This is a subtle but important point, given what we know about the biology of senescence: Gene expression is an imperfect marker for the extent of senescence within a tissue: A given amount of RNA could mean a small number of cells with intense expression or a larger number of cells with lower expression.

Distinguishing between these alternatives may be clinically important, depending on whether the increased senescence is causing the poorer transplant performance — and if so, why? Regeneration is likely necessary for optimal organ performance after a transplant; since senescent cells are permanently nondividing, the presence of a large number of them would predict poorer regenerative capacity. Alternatively (though not mutually exclusively) the protein factors secreted by senescent cells might have deleterious consequences on the function of the tissue itself, and this might interfere with transplant efficacy.

Figuring out which is more decisive — the number of senescent cells in a tissue, or their aggregate production of secreted factors — will become very important if we’re someday able to selectively destroy senescent cells. In the “increased numbers” case, such treatments wouldn’t help (the cells are equally unable to divide whether they’re alive or not), but in the “increased secretion” case, anti-senescence therapeutics could make the difference between success and failure in organ transplants of many kinds.



  1. The recent paper –
    “Motif module map reveals enforcement
    of aging by continual NF-kappaB activity”
    – demonstrated that old skin can be (at least morphologically) rejuvenated by local NF-kappaB blockade. The paper also indicates NF-kB is upregulated in aged kidney tissues. Is it possible that the aged kidney would respond favorably to down regulation of NF-kB? i.e., some regrowth, reduced proteolytic enzymes, etc.

  2. I am curious how this report correlates with the phenomenon of serial transplantation of skin in mice? I seem to recall skin can be passaged from old to young multiple times in immune matched animals such that the transplanted skin patch far outlives the original donor.

  3. That’s a great question, Gary. It would be interesting to compare the data between the two types of studies. Off the top of my head, I can imagine a couple of explanations:

    (1) Skin and kidney are different enough tissues that they give different results.

    (2) The skin grafts did fail more often when they were from old donors, but occasionally they were able to propagate for a long time, and this is how the result was reported. In other words, the failure rate rose with graft age but the maximum survival of a graft was still larger than the average lifespan of a mouse.

    Anyone want to dig up these old studies and check them out?

  4. I was just wondering if (very) long lived animals (turtles, whales, parrots) perhaps have by default a lesser secretion of such products by senescent cells.

  5. As you suggest, it seems to this old engineer that the best way to unravel the mystery that is aging would be to look across species. Since there is a wide lifespan disparity even within Class Mammalia (say, mice and bats) and among birds (finches and petrels) it seems altogether logical to be methodically comparing putative aging mechanisms between such examples. I am frustrated beyond words that hardly anybody seems to care enough to do this. Why is this so hard?

  6. Great questions. Mstudent: We don’t know yet, but we will, hopefully soon. Gary: You’ll be pleased to know that a project is currently underway to do exactly the sort of comparative work you’re hungry for. I’m directly involved. Early days but an outline of the concept is here.

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