The Potential Use of Cell Therapies to Treat Immunosenescence

Immunosenescence is the name given to the decline of immune system effectiveness with aging, a large component of the frailty that arises in later life. This decline is partially a result of a failing supply of new immune cells, and partially a result of a growing misconfiguration of the immune system as a whole, driven by life-long exposure to infections. On this second front, persistent infection by herpesviruses such as cytomegalovirus appears to be particularly problematic, the cause of large fractions of the immune cell population in an old individual becoming specialized and unable to react to new threats. This open access paper considers the potential role for cell therapies in reversing immunosenescence, with possibilities that go beyond merely generating and delivering new immune cells to the patient on a regular basis:

Human life expectancy has increased from 40 to 80 years of age just over the past 2 centuries largely due to medical advances. However, it is likely that the human immune system did not evolve to protect the host over such an extended lifespan. Immunosenescence is a term that describes the changes in the immune system that are seen in the aging population. The hallmarks of immunosenescence include a reduced capability to respond to new antigens, increased memory responses, and a lingering level of low-grade inflammation that has been termed "inflamm-aging." Decline of the immune system is associated with increased incidence of infection, immune disease, and cancer in the elderly. While immunosenescence is often described as a decline in the number and function of immune cells, myeloid cells have been shown to increase in the aged population and some secreted peptides are also expressed in greater amounts. Therefore, it is important to keep in mind that immunosenescence is more appropriately conceptualized as a change in the actions of the immune system, rather than an overall decline of all functions and constituents.

The immune system is generated and maintained by asymmetric division of multipotent haematopoietic stem cells (HSCs) in the bone marrow. The immune system has 2 arms, the innate and the adaptive systems, which work together to eliminate pathogens and neoplastic cells, respond to vaccination, and regulate processes such as tissue turn over and wound healing. Increasing evidence shows that HSCs themselves undergo age-related changes and have a limited replicative lifespan. HSC aging was demonstrated by serial transplantation of whole bone marrow, which only supported 4-6 rounds of transplantation, suggesting the possibility of stem cell exhaustion or replicative senescence. In addition, accumulation of DNA damage has a profound impact on HSCs, leading to loss of proliferation, diminished self-renewal, increased apoptosis, and subsequent exhaustion. Differentiation of the HSCs is also affected by aging, where HSCs committed to the myeloid lineage outnumber lymphoid cells in both mice and men.

Rejuvenating the HSCs might improve some of the dysfunction of both macrophages and T-cells, as well as many other cell types, observed in aging. Bone marrow transplantation from a young donor to an elderly patient could be used to rejuvenate the exhausted, aged progenitor pool. However, imperfect tissue matches often lead to rejection and even graft-vs.-host disease, a major hurdle to overcome in many fields of study. Induced pluripotent stem cells (iPSCs) could theoretically be used to generate HSCs from a patient's own cells, thereby eliminating donor-recipient mismatch. Techniques to differentiate HSCs from iPS cells exist, but efficiency and safety are major hurdles that this technology must yet overcome. In addition, genetic reprogramming will likely need to take place ex vivo to prevent collapse of organ function in the intermediate, undifferentiated cell state, so repopulation of tissue resident macrophages and lymphocytes will take several weeks or months from a single bone marrow transplantation. Also, effectiveness of rejuvenated HSCs would be limited by thymic output for T-cells and would likely not replace tissue resident macrophages, which are self-sustaining. However, repopulating the bone marrow with autologous iPSC-derived HSCs is a promising approach to rejuvenating the majority of immune system, especially the innate effector response.

The thymus begins to significantly deteriorate around 10 years of age in humans, and likely plays a role in the decline of the immune system, especially the diversity of the T-cell repertoire, during aging. Rejuvenating or somehow regulating thymic output is an intriguing approach to combat age-related decline of T-cells. Approaches to replacing or regenerating the thymus include tissue and cell transplantation. Transplantation of cultured thymic tissue from human cadavers into the kidney capsule of patients with DiGeorge syndrome successfully restored immune function for up to 10 years. However there are limitations to this approach for treating the aging population due to lack of donated tissue, invasive surgery, and tissue rejection. Regenerative medicine, including tissue engineering and cell and gene therapy, offer alternative approaches to replacing the thymus. Many groups have identified multipotent progenitors, termed thymic epithelial cells (TEC), that can grow into a 3-dimensional thymus and support normal T-cell development when transplanted into the kidney capsule. Human TECs have yet to be isolated in sufficient numbers, however protocols to push human embryonic stem cells toward TEC lineage are becoming consistently more efficient.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879890/

Comments

This paper acknowledges past evidence that DNA damage is important in intrinsic cell aging (not the SENS RF view). But at least in this case it is not important if the cells are going to be wiped out and replaced. If DNA damage is a part of aging then would this approach work in other tissues of the body?

http://dx.doi.org/10.1017/S1462399409001197

I hope that the group that the SENS foundation partially funded to engineer replacement thymus tissue have some results to publish soon.

And I hope that this approach to resetting the immune system becomes available sooner rather than later. I recently had a friend aged 35 develop type 1 diabetes.

Posted by: jim at August 30th, 2016 7:10 AM

Hey there !

In the mean time of the arrival of immunotherapies,
we can improve your immune system. The immune system
is mostly the lymph nodes, the blood white cells, the intestinal
immune cells, the bone marrow immune/stem cells and the
thymus. But out of all of these, the largest effectors
are the bone marrow and thymus. Improving bones minerality will
already improve bone marrow immune output capacity, that means
taking certain minerals like Magnesium or Calcium (there is a
ratio of Mg to Ca), vitamin D3 increases bone minerality and
thus, improves immune system. Another very powerful one
is darkness therapy (inversely of light UV creating D3),
darkness therapy removes capability to acquire D3 (take some),
but has a massive effect on thymus (one study showed
that darkness increases thymus output and size by 300%,
meaning it litterally reverses thymus involution with age - which
is causal to immunosenescence. By having a stronger thymus (with an already stronger bone/marrow, the two work in tandem with T-cells formation), this increases
the power of T-cells, Nk-cells, neutrophils, white cell leukocytes and lymphocytes, macrophages cells. Increasing the Cancer-Killing power of T-cells. Darkness increases melatonin levels and depigments skin, which melatonin from pineal gland, Acts on
T-cells (the same study suggested that melatonin can act on T-cells and is direct
effector on Thymus. Hence, darkness increasing thymus and melatonin levels, and as such, immunity/killing cancer power. Melatonin has a host of other functions such as antioxidant and creating sleep). Who said living like a monk or vampire in the dark was so bad, turns out, it isn't, what's so bad is getting too much sun UV exposure - creating skin cancer - which, ironically, is good for D3 creation/obtention - but ironically, darkness takes that away by removing ray UV to D3 skin creation from no light exposure (blood D3 is inverse correlation to cancer advancement and inhibits them, synthetic D3 combined with dark therapy is better, you get the best of both worlds). The ligh/darkness cycle is important to maintain CREBS/Circadian clock cycle, but it seems we can indulge in more darkness than lightness; just be careful, darkness slows metabolism (like a CR torpid effect)/lightness increases metabolism (darkness = depression/Dizzy/sleepy/amorph symptoms. lightness = uppity/happy/cells energized by light).

Posted by: CANanonymity at August 30th, 2016 1:19 PM

PS: One warning, I used to take synthetic melatonin to improve sleep and increase TAC power (total antioxidant power), I don't anymore. Melatonin, in one study, was shown to accelerate atherosclerosis (when in fact, it does act as antioxidant and improves LDL oxidation lag time); I'm guessing it altered cholesterol negatively and as such increased atherosclerosis. Same thing for metformin, helpful for diabetes, but found out in another study it accelerates late Alzheimer's; this is rather Strange since by reducing AGEs, HbA1c and glucose levels, Alzheimer's amyloid formation is reduced from lowered oxidative-stress (By AGEs and hyperglycemia/glycation/glycoxidation). I am guessing metformin alters cholesterol/homocysteine, thus, again could become bad and increase Alzheimer's (since some of the brain consists of cholesterol). So for people who were wondering if metformin reverses aging and will make anyone reach 100, sadly, no, from that study it Increased Alzheimer's; most Alzheimer's people never reach much beyond 110. As for studies who showed lifespan extension of 'above control', these were too small samples it seems. Perhaps, in healthy people, metformin then become helpful but in diabetics it can turn out bad instead of helping it seems. My father went back on metformin as he said Nothing helps, he was off of it for a while but blood glucose rose up steadly again; so was back on metformin, and things now, stable again. I just worry of the effects on his brain (my uncle died of Alzheimer's, but he's of course totally unrelated genetically to father).

Posted by: CANanonymity at August 30th, 2016 1:44 PM

@Jim SENS does acknowledge DNA damage as a cause for cellular senescence.
Induced pluripotent stem cells are sensitive to DNA damage, so stem cell therapies with reprogrammed cells can provide cells for replacement with good quality DNA.

I'm more concerned about mosaicism than DNA damage to be honest.

Posted by: Anonymoose at August 30th, 2016 2:35 PM

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