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“To everything there is a season, and a time for every purpose under the heaven: a time to be born, and a time to die…”

– Ecclesiastes Chapter 3

The sage of Ecclesiastes wrestled with cold, hard truths that lacked instant rebuttals. He lamented, “There is nothing new under the sun.” One such thing that hasn’t changed in millennia is humans’ quest to postpone their own decline and demise. Or at least… render our final “marginal decade” less fraught with the toll of chronic conditions like cardiovascular disease, cancer, arthritis, impaired vision, osteoporosis, and dementia. As we age, each injury and illness tends to hit just a little harder, and each recovery takes just a little longer. Yet despite our best intentions, life remains fragile, precious, and ever-so-fleeting.

There are those who talk seriously about living to age 150+ with the help of nanotechnology, genetic augments, and cybernetic brain uploads—things mostly still in the realm of sci-fi. We wish them luck, but this blog is not about that ambitious goal. Instead, we’ll briefly explore some exemplary findings with mesenchymal stem/stromal cells (MSCs) and their secretomes, which shine a light on the prospect that we might enjoy more life in our years, if not more years in our life (yet).

Why We Age

When human cells divide to produce other cells, tissues, organs, and entire bodies, replication errors initially pop up at a rate of approximately 100,000 mutations per cell [1]. Thankfully, these are mostly proof-read and corrected, leaving only about 0.1-10 actual errors per division. [2] Nevertheless, an adult human is made of about 37 trillion cells, each having divided a rough average of 45 times (some much more, some far fewer) since the zygote stage. Hence, over time, our genetic “hardware” in the somatic cell genomes acquire dings, and further, their telomeres erode until the Hayflick limit of ~60 finite population doublings is reached. [3] Perhaps as importantly, epigenetic decorations on individual cell genomes (e.g., the genetic “software”) affect patterns of specific gene expression, which, in turn, determine cell identity and function. [4] Total restoration of the prior chromatin state does not necessarily follow from high-fidelity sequence repair of DNA damage, leading to epigenetic scarring [5] and “chromatin fatigue.” [6] The information “noise” that results from desynchronized and garbled gene transcription may blur the phenotypes of daughter cells, [7] rendering them variably able to function in a concerted manner within a full tissue. [8] Finally, the powerhouse organelles of our cells, mitochondria, become less efficient at converting nutrition into energy due to toxic free radicals that are both the products of *AND* the cause of a “rusting” oxphos engine.

Thus, the hardware, software, and batteries of cells gradually and stochastically grind down until they trigger their own suicide program, apoptosis, or simply stop going, i.e., senescence (Figure 1). Senescent cells are sometimes called “zombie” cells, which can be associated with a “senescence-associated secretory phenotype” or SASP. [9] Although different cells present different SASPs under different circumstances, they do tend to spread inflammation, fibrosis, “inflammaging,” and secondary senescence across to neighboring, healthy cells [10] via their secreted factors and extracellular vesicles (EVs). It stands to reason that selective deletion of senescent cells, ablation of SASP, and replacement of damaged cells with younger or more robust ones might slow progression of chronic diseases of aging. The last decade of experiments has affirmed these hypotheses. Let’s see next how MSCs and their EVs (sometimes called “exosomes”) could play a key role in aging and how to block it.

Figure 1, A STRING-db visualized network [11] (to tinker with it yourself, see permalink: HERE) of senescence-related gene products (input, genes from GO:0090398, cellular senescence).

Can MSCs Help?

MSCs are multipotent, able to differentiate into bone, fat, cartilage, and perhaps several other cell types. [12]  They’re capable of many additional rounds of cell division, stored in the human body until injury or disease recalls them into “active duty.” [13] They then can help plug holes in damaged blood vessels, donate mitochondria to exhausted repair cells, and differentiate into bone, cartilage, adipocytes, or fibroblasts. Their secretomes include cytokines, growth factors, and extracellular vesicles (EVs; including exosomes) that are anti-inflammatory and/or pro-angiogenic, and these recruit a choreographed repertoire of wound healing and regenerative cellular activities. [14]

MSCs’ adaptability to tissue culture and innate hardiness makes them excellent supporting cells to populate scaffolds for multi-cell type tissue engineering applications like myocardium, liver, cornea, trachea, aortas, and skin. For example, MSCs, their EVs, and their conditioned media promote seeding of tissue engineered vascular grafts (TEVGs) that are functional in live mice, promoting smooth muscle cell retention and recruitment. [15, 16] In another example, muscle-derived MSCs delivered within a bioprinted collagen gel improved left ventricular (LV) dysfunction in a rat model. [17] The objective is that such replacement “spare parts” might one day treat coronary artery disease, aortic aneurysms, or heart failure in humans.

Cooling Zombie Fires

Long-lived senescent cells are thought to cause chronic inflammation, a biological process with annotated patterns of gene expression (GO:0002544, example STRING network HERE). With in vivo animal studies and in human patients, the benefit of MSC preparations for inflammatory conditions such as GvHD (e.g., Ryoncil®) [18, 19] or severe osteoarthritis (e.g., Cartistem®) [20] is now well established. Their mechanism of action is not likely from a single effector, but instead, a paracrine cocktail that amplifies its downstream activities in feedback between multiple immune cell types.

According to MSCs’ nominal, physiological role in wound healing resolution, their secreted factors swiftly dampen over-exuberant immune activity in lesions while recruiting cells needed for angiogenesis. [21] These include TSG-6, prostaglandin E₂ (PGE₂), IL-10, and IL1RA, which counteract TNF-a and NF-κB signaling and polarize local macrophages towards an M2 phenotype. In addition, MSCs robustly express CD73, which is part of an enzyme pathway (ATP/ADP → AMP → adenosine) that ablates the extracellular ATP damage signal and converts it to adenosine, an anti-inflammatory metabolite. [22] Another potent MSC factor is IDO1 (indoleamine-2,3-dioxygenase), which converts tryptophan to kynurenine, promoting tolerance to self through T cell suppression [23] and/or Treg mobilization. [24] Engulfment of shed fetal mesenchymal stromal cells by maternal macrophages [25, 26, 27] impels these innate immune cells to ramp up IDO1 activity and thus protect the developing baby from immune rejection. MSCs also express heme oxygenase-1 (HO-1), which detoxifies heme and produces bilirubin, which neutralizes damaging peroxyl free radicals.

The question of whether MSCs’ potency against SASP and inflammaging degrades with age (and whether replacement with healthy MSCs can ameliorate it) is being explored. [28, 29, 30] MSC-specific SASP markers have been surveyed. [31, 32] Paracrine activity of the aged MSCs’ SASP may impair optimal function for a tissue such as bone marrow, impacting clonogenic potential of hematopoietic stem and progenitor cells (HSPCs). [33] MSCs taken from patients with type II diabetes or metabolic syndrome show more signs of diffuse inflammatory stress (e.g., CD44) and senescence markers, and are impaired in regenerative capacity. [34] Thus, the history and sources of any bank of MSCs in therapeutic development are likely to matter. [35] Since implantation of even small numbers of senescent cells into young mice causes their premature aging and administration of senolytic cocktails ablates it, [36] therapeutic elimination of damaged MSCs via such drugs is of increasing interest. [37, 38, 39] Is it any surprise that injected MSCs seem to reduce aging and SASP in mice? [40] Data from smaller human trials vs. aging frailty suggest the effect might also be worth investigating further. [41, 42]

MSCs to Tame Fibrosis

Prolonged inflammatory cues can lead to fibrotic scarring, a molecular process closely intertwined with human aging.  [43] It is hypothesized that this may occur due to a shift away from CD4⁺ T cells and towards Th17 type T cells near the site of injury or infection. [44] In turn, a Th17 polarized milieu engages IL-17 receptors on local stromal cells, synergizes with IL-6, IL-13, and TGF-β, and drives persistent myofibroblast activation and collagen deposition across tissues. [45] Gradual drift towards a skewed TH17/Treg ratio (coincidentally?) correlates with the inevitable involution of the thymus as humans age. [46] In addition, SASP factors alone promote the differentiation and activation of myofibroblasts, causing fibrotic spread across a tissue. [47] In the developed world, a surprising 45% of all mortality is driven by severe fibroproliferative disease processes of the inner organs and circulatory system, a toll that rivals or exceeds cancer. [48, 49]

The secretome of MSCs exerts potent regenerative and/or protective activity against preclinical models of fibrosis in animals or 3D tissue constructs, including liver damage, [50, 51, 52] bleomycin-treated lung, [53] ovarian insufficiency/PCOS, [54, 55] heart disease, [56, 57] and renal failure/CKD. [58] At least 20 posted human clinical trials using MSCs, their conditioned media, or their EVs/exosomes have been directly leveraged against fibrotic indications since 2011. [59]  In addition to direct clinical applications, MSCs have been used clinically to “educate” other cell types ex vivo, such as macrophages, in adoptive transfer therapies. In an exemplar of “MSC 2.0” applications, [60] Dr. Ashish Patel and colleagues at King’s College London employed injected doses of monocytes in a clinical trial that were primed into an antifibrotic and pro-angiogenic phenotype via prior co-culture with MSCs. [61] In this example, the MSCs served not as the therapeutic agent, but rather a necessary accessory enroute to the final monocyte product. [62]

Brother Can You Spare a Mito 🎶

Mitochondria are central to diseases of aging, and to normal aging, in general. [3] When intracellular quality control (mitophagy/biogenesis) begins to unravel as a consequence of mtDNA mutation, persistent electron transport chain dysfunction leads to excess reactive oxygen species (ROS), membrane depolarization, and tipping cells toward apoptosis—or a senescent, pro-inflammatory state. Brief physiologic uncoupling of electron transport can reduce ROS, but chronic depolarization is maladaptive. [63] On the other hand, MSCs have a major role in “donating” fresh, functional mitochondria to exhausted cells as part of their orchestration of wound healing and infection response. [64, 65] This can occur via tunnelling nanotubes, [65, 66] larger vesicles, [67] cell fusions, [68] or transient cell-cell contacts. [68, 69] In addition, secreted molecular signaling factors from MSCs tend to potently improve the quality control of recipient cells, such as per chemotherapy-damaged granulosa cells. [70] Given that mitochondria, themselves, can be transplanted to recipient cells “naked” (i.e., without further encapsulation and manipulation), [71] MSCs have been turned to as producer cells for “mito-drugs” that are now advancing into human clinical trials. [64]

Nano Vesicles—but Macro Impact with MSC-EVs

Because of their ability to display [72] or encapsulate [73] biologically active molecular cargos, EVs/exosomes comprise an important secretome component of MSCs that may account for much of these cells’ therapeutic potential. [74, 75] EVs can also be artificially engineered with both targeting as well as signaling molecules, and safely injected into test animals for preclinical initiatives. [76, 77, 78] Since EVs can be practically extracted from MSC conditioned media and purified as stockpiled drug doses with standardized QC that bypass concerns of cell fragility and product variability, MSC-EVs have served as the active agents of more than 100 posted clinical trials since 2011. [59] Related human trials, patent applications, and journal publications have increased at a geometric rate in the last 10-15 years, and early data are encouraging. [79]

What do EVs have to do with anti-aging therapy? Perhaps a good first glance is the study by investigators from Scripps Florida and other sites (Dorronsoro et al., 2021). [80] Work in this publication demonstrated that IP-injected MSC-EVs from young mice can reduce cellular senescence in vitro and in vivo and extend health span in progeroid (Ercc1−/∆) mouse models of aging. Overall, lifespan was also extended. Some of this senotherapeutic effect may have been due to the encapsulated miRNAs that targeted pathways such as p53, PTEN, Myc, and IGF-1R. Although this was one of the first observations that EVs from MSCs could modulate lifespan, a notable prior work loaded plasma-derived EVs with extracellular nicotinamide phosphoribosyltransferase (eNAMPT), injected them into aged female mice, and likewise observed substantial increases in lifespan and physical fitness. [81]  A number of other studies in animals have provided evidence that administered MSC-EVs can ameliorate cortical injury in aged monkeys, [82] cognitive impairment in Alzheimer’s mouse models, [83] neuroprotection in SAMP8 mice mouse models of premature aging, [84] UVB skin photoaging in mice, [85] and ischemic stroke in rats, [86] to name a few. Although it would be tantalizing to learn of human clinical trials for other indications being initiated (e.g., Hutchinson-Gilford progeria), the first studies involving humans and MSC-EVs seem to be directed at skin aging.

Doing It with Might

“Whatever your hand finds to do, do it with your might; for there is no work or device or knowledge or wisdom in the grave where you are going,” says the sage, returning with this cheerful earful in Ecclesiastes Chapter 9. Has interdisciplinary aging research gained recent momentum from data to show that “the grave” could be slightly less inconveniently timed nowadays? Maybe, but no matter! Even an ancient sage could agree that the challenge to relieve misery through regenerative medicine research against chronic aging diseases should remain as urgent (and full of “might”) as ever. RoosterBio’s many partners (cited in this blog and elsewhere) bring full rigor, creativity, and collaboration to solving the biology of aging.

As cell and gene therapy moves from promise to practice, every discovery brings us closer to therapies that not only extend years, but restore vitality to them. RoosterBio is proud to help build the manufacturing foundations beneath that progress by providing the cells, media systems, and process expertise for MSCs and EVs/exosomes that allow ideas to scale with confidence. Together, we can turn the science of aging into the art of renewal!

This blog provided evidence that certain MSC or MSC-EV tissues and “origin stories” could affect their performance in prospective in vivo studies. To learn more on how to empirically evaluate the best-fit cell vial for your intended application, check out our Donor & Tissue Screening Kits, featuring multiple MSC cell donors spanning umbilical cord, adipose, and bone marrow sources.

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