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大衛·辛克萊 (David Sinclair) 2019 年十月十日股溝視頻 "壽命: 我們為什麼會老化,為什麼我們不必" 的素人導視

李弘謙

2020 年三月一日

我認為這個演講非常有趣,內容豐富,令人振奮和鼓舞人心。 不是因為大衛·辛克萊(David Sinclair)暗示我們可能永遠活著(他不是),而是因為他告訴我們有可能健康地衰老,也許在不久的將來,有可能使人體的某些老化的部位或器官恢復活力。

最近,為了標出辛克萊演講的要點以供將來參考,我重新看了一遍他的視頻。 我所做的紀錄附在本文後面文獻錄之前。

儘管辛克萊的是對一般聽眾的演講,但是相信多數非專業的素人可能有很多地方不易聽懂,特別是那些以前沒有聽說過表觀基因組/表觀基因體這個名詞的人;這是辛克萊演講的關鍵的關鍵名詞。

在這篇對象是素人的部落格裡,我提供一些有關表觀基因體和相關名詞,些包括幹細胞、四個山中因子(the four Yamanaka factors)、細胞“重編程”(reprograming) 等的通識性背景知識。這些名詞對辛克萊的發現至關重要。

十分巧合,我過去十年的工作(遠遠低於辛克萊工作的水平)使我接觸了這些主題。

幹細胞與細胞分化

細胞分化導致細胞特異性; 有特異性的細胞(例如皮膚細胞,神經細胞,肝細胞)負責執行某些特定的生物功能。

人類的生命始於單個受精卵,受精卵經過許多階段的分裂和分化,最終生長和發展成為完整的身體。 在這裡,我們可以將分化理解為專業化。 細胞完成分化流程之後成為具有特異性的成體細胞。

幹細胞尚完成分化流程的細胞, 它具有繼續分化的潛能。 分化的潛能有很多層次,因此有多層次的幹細胞。 最高層次、所有幹細胞之母就是受精卵,比它低一級的是胚胎幹細胞。

剛出生的嬰兒中幾乎所有細胞都已經是成體細胞:神經細胞,肺細胞,肝細胞,皮膚細胞等。 每一類型的成體細胞都有它的特異性,具有一種功能,執行一種工作,而不能執行任何其它的工作。 但是它們都來自單一個受精卵,並且都具有與受精卵完全相同的DNA。 那麼,兩種有特異性的細胞到底有什麼不同呢?

讓我們將細胞中的DNA視為計算機的硬碟(11:50)。 就如同當細胞要執行某項任務時,會讀取DNA上的某些基因密碼,將他們「表達」成執行該項任務所需要的蛋白質(也就是細胞裡的奈米機器),當用戶要用計算機做某件事時,會在硬盤上讀取、或打開某些應用程式,使用它們執行任務。

就執行某特定任務的需求,用戶會打開特定的一個或一組應用程式,同時不動用任何其它程式。 同樣,在具有特異性的細胞中,只會表達執行該細胞指定任務所需要的基因,不會表達任何其它基因。

然而,以上的比喻並不完整。 計算機的用戶執行一項任務之後可以隨時改變主意,並打開另一個(組)應用程式子執行另一項與之前完全不同的任務。 有特異性的細胞不能,它永遠只能表達一組特定的基因,執行同一件特定的任務。 我們需要更高層次的比喻。

考慮一家生產和銷售多種產品的大公司。 其所有知識產權都存儲在總公司硬盤中。 公司的各個部門分別各自負責一個產品,並且都可以從公司硬盤攝取資料, 但非全部資料: 每個部門只能從硬盤攝取與其所負責產品相關的資料,除此之外硬盤的其餘部分,對該部門而言均已鎖碼。 如此可以確保公司有某特定任務的部門能順利的執行與該任務有關的一切工作,而不能執行任何其它與該任務無關的工作。

人體的管理和上述的大公司完全相同。有特異性的細胞,除了執行該細胞指定任務所需要的基因可以表達之外,其它所有與該任務無關的基因都在DNA上會被鎖碼,在該細胞裡不能表達。 如此可以確保在它整個生命中,一個成體細胞可以執行它被指定的工作,也只能執行那項工作。

在是人體(或任何多細胞物種的身體)構成的宇宙裡,運行的政治制度是極端威權主義。在這個宇宙中細胞不是具有自由意志的個體,而是注定要一生只做一項工作的機器人。

我們可以猜測,這個鎖碼現像是在漫長的進化過程中發展出來的。一位有它,一個生物體的各個不同組織才能有現實中呈現的極高的穩定性。

表觀基因體

表觀基因體經由部分DNA的鎖碼賦予細胞其特異性

表觀基因體 (Epigenome) (10:10)是不涉及改動DNA而影響細胞功能的所有事物的泛稱。 它有兩個主要功能:包裝DNA與經由鎖碼/解鎖部分DNA以賦予細胞特異性。

伸展至全長的人類基因組大約1.8米長。 當包裝成染色體時,每個大約長一至二微米。

包括DNA在內的基因組以高度精確的數位化方式處理資訊。表觀基因組則不同,它以模擬化的方式處理資訊(11:09),同時它的精確度是概率性的。 也就是說,表觀基因組沒有使用一個特定的鑰匙鎖碼或解鎖DNA上的一個特定或精確的位置。 而是用不論如何達成的一系列化學作用,鎖碼或解鎖DNA上的一個概略的區域。

當細胞中的DNA被部分鎖碼以賦予細胞的特異性時,DNA會顯示出與細胞身份相配的近似鎖碼特徵。表觀基因組的鎖定特徵是可遺傳的。 同一對同卵雙胞胎可能因具有不同鎖碼特徵的表觀基因組,而有相同的基因型但是不同的表現型。

在辛克萊影視10:10處,有一幅展示了表觀基因組的漫畫:基因組(或DNA)被包裹在捲軸上。 每個捲軸均由四種特殊蛋白質組成,這些蛋白質通過與被包裹在其上的DNA的化學相互作用來執行鎖碼功能。

山中與分化後成體細胞的重編程

已經分化的成體細胞可以經由“重編程”倒退至較早的干細胞狀態

就如同基因組具有一個信息系統,其內容(主要是基因)定義物種一樣,表觀基因組也具有一個信息系統,其內容(基因鎖碼特徵)定義細胞特異性。 基因組信息的流失可能導致胚胎衰竭或個體畸形或患病,而表觀基因組信息的流失將導致細胞失去它明顯的特異性。

在2006年和2007年,山中伸彌 (Yamanaka Shin'ji ) 和他的研究團隊在《細胞》期刊上發表了兩篇論文,報告說他們將從小鼠 [1] 和人 [2] 身上提取的成年細胞成功的重編程為「誘導性多能幹細胞」, 具有比全能胚胎幹細胞低一級的分化潛力。

山中的工作顯示,如果在將通常鎖定在成體細胞中被鎖定的四個特定基因(稱為四個山中因子)(22:32)經人工輸入到成年細胞中,就會啟動一個過程,在該過程中,細胞經過多達 60代的繁殖,會逐步將表觀基因組在DNA上的鎖碼完全解除,因而將細胞轉變為幹細胞。這種被稱為誘導性多能幹細胞的細胞具有分化成各種不同於之前的成年細胞的潛能。

山中因發表了這兩篇重磅炸彈在50歲時獲得了2012年諾貝爾生理學或醫學獎(22:04)。

辛克萊的老化資訊理論

表觀基因組的資訊流失導致細胞老化 (8:33)

就如同基因組具有一個信息系統,其內容(主要是基因)定義物種一樣,表觀基因組也具有一個信息系統,其內容(基因鎖碼特徵)定義細胞特異性。 基因組信息的流失可能導致胚胎衰竭或個體畸形或患病,而表觀基因組信息的流失將導致細胞失去它明顯的特異性。

根據辛克萊的老化資訊理論,細胞失去表觀基因組賦予它的基因鎖碼特徵是細胞老化的原因。 辛克萊說(12:54)“細胞會因此而失去了特異性……老年人的神經細胞不再完全是神經細胞,而可能部分是皮膚細胞。

就細胞特異性而言,失去表觀遺傳資訊意味著DNA的基因鎖碼特徵被破壞。 即,應該被鎖碼的某些DNA部分沒有被鎖碼,不應該被鎖碼的有些部分被鎖碼。 結果是細胞可能不再正確地執行其應做的任務,而同時又糟糕地執行了它不執行的任務。

經由老鼠模型實驗,辛克萊團隊研發了一種使表觀基因組流失資訊的方法,從而導致老鼠的生物衰老速度比正常情形按鐘錶時間的衰老速度快得多。

如何使表觀遺傳資訊流失

重複的雙鏈DNA斷裂導致表觀基因組資訊流失

回顧一下,DNA是雙鏈螺旋。 當DNA遭受雙鏈斷裂時,會啟動表觀基因組將一件機器(一組大分子)搬移至DNA的斷裂位點將斷裂修復,之後該件機器會返回原先在表觀基因組基礎設施內的正常存放位點。

但是,有時這種返回動作會執行不完整,導致表觀基因組遭受輕微的損壞。 辛克萊團隊以重複在隨機DNA位點使雙鏈斷裂的方法,使表觀基因組因此承受的累積損傷,足夠破壞表觀基因組的資訊系統,而最終導致細胞的基因鎖碼特徵受損,從而使細胞失去其特異性。

在兩篇論文中,辛克萊(兩個不同的)團隊驗證,這種破壞表觀基因組資訊系統的流程 會導緻小鼠產生變化,這些變化在基因型上(DNA和基因)[3] 與表現型上(外觀,精神和身體能力)[4] 都與是正常衰老引起的變化匹配。

辛克萊的“逆轉老化”實驗

被青光眼或老年致盲的小鼠的視力被恢復到年輕狀態

如果老化是由於細胞失去其特異性,或者說是由於細胞中DNA鎖碼特徵被破而引起的,那麼,通過糾正鎖碼特徵可以逆轉老化嗎? 這看似是件沒有希望的任務,因為DNA鎖碼特徵有無限的可能被擾亂,而當我們不確知什麼是細胞的正確鎖碼特徵時,要復原它就更難了。

通過恢復人為誘發青光眼致盲與正常老化視神經被粉碎的小鼠的視力的實驗 [5] (26:34),辛克萊團隊證明至少在某些特定情況下,逆轉老化是可能的。

辛克萊團隊用四個山中因子中的三個以部分重編程的方法將老化/損壞的視覺細胞還原至(他們認為是)年輕/健康狀態來實現這個壯舉(23:30)辛克萊認為其它這類“逆轉老化”或許也可以實,因為“舊組織忠實的保留了逆轉老化所需要的年輕的表觀基因資訊(亦即DNA 鎖碼特徵)”(27:08)。

這種抽象概念可能的實際過程如下:正確的DNA 鎖碼特徵經過長時間的存在,或許留下了特徵的“凹槽”,以致在鎖碼特徵遭受破壞後構成比較容易返回的路徑。我們可以猜測,在辛克萊團隊的實驗中,通過徐緩地執行重新編程,將被擾亂的表觀基因組輕輕地導回到了年輕的狀態。

"最好的方法是降低進食次數和多運動"

這是辛克萊爾問自己時的回答:“如果不想要醫生建議服用什麼將抗補品,該怎麼辦?” (30:05)

辛克萊的演講在34:50結束。 之後是問答時段。 問答很有趣,但是專業性較高(可以參閱下面的內容)


以下是技術性較高的若干相關議題。最後一段是

大衛·辛克萊健康補品。

Why did Sinclair use only three Yamanaka factors, not four, in his age reversal reprogramming?

Sinclair et al. only wanted to reprogram the cell to its youthful adult state, not to its very early stem cell state, as Yamanaka did. The fourth Yamanaka factor left out in Sinclair reprogramming procedure is oncogenic, namely, it promotes cancer growth.

It turns out induced stem cells when left undifferentiated have a significant chance of turning tumorous. One reason is that cancer cells and stem cells share a crucial property, immortality: the mechanism leading to cell death is turned off in both. (The four Yamanaka factors, actually for genes, are Oct3/4, Sox2, Klf4, c-Myc. The cancer causing one not used by Sinclair is c-Myc.)

How original is Sinclair's work reported here?

After Yamanaka showed how to reprogram a cell, many people have used the technique to do many things, including using the four Yamanaka factors to rejuvenating cells.

The important messages reported in Sinclair's talk are based on original work done by his group on mice: his Information Theory of Aging; demonstrating that double-strand breakage of DNA leads to disruption of the epigenome that can cause a cells in the mouse to lose their identities, such that a chronologically young mouse would show signs, physiologically [3] and molecularly [4], very similar to those of an old mouse; and his "age reversal" experiments showing that using three Yamanaka factors to reprogram aged/damaged cells can restore the vision of age/glaucoma affected mice [5].

Mice are not exactly human, but biologically the two species are awfully close and what Sinclair et al. see in mice has a good chance to be true in human, too. But that is not a given. Sinclair has had many of his papers published in first tier journals including Cell and Nature, quite likely one or more of these three preprints will be, too.

How are Sinclair's work/claim received?

Personally, I think the works reported in [3, 4, 5] are solid, in fact first class. Sinclair's many public talks, most given to promote his book (same title as the talk), seem to be raising some eyebrows [Has Harvard's David Sinclair Found the Fountain of Youth?] as well winning kudos [Can David Sinclair cure old age?].

It could be that some of Sinclair's distractors object to his hyperbole, such as naming his findings a theory, and using non-biological metaphor such as Shannon's information theory to describe how the epigenome sets cell identity, or to his too-strong advocacy that aging is a medical condition that can be treated, but not something that is natural and should be left alone.

Sinclair's Shannon Information metaphor

(This section a is a bit more technical than others) Sinclair believes that underlying the success of his "age reversal" experiments in restoring the vision of old/glaucoma affected mice is the existence of an epigenetic correction system (23:30) in the cell similar to the Shannon's correction system in communication (20:44) that allows for arbitrary low transmission error, making today's IT industry possible.

My feeling is that this belief is misplaced. This notion in fact seems to contradict what Sinclair says about epigenome information: it is analogue (11:09), not digital, whereas Shannon's theory deals with digital information.

I also feel that evolution would not have produced such a correction system, not because it is elaborate, but because there was no need for it. During development a cell acquires its identity through differentiation, and functional stability requires that it stays with its designate identity through its entire life.

More likely Sinclair's mouse vision experiments succeeded because of the "groove" scenario mentioned earlier.

The lack of a correction system advocated by Sinclair, if true, can be compensated, say, by taking records of the epigenome locking patterns of the various cell types of a youthful individual, to be used for Sinclair-type cell reprogramming when that individual is older.

大衛·辛克萊健康補品

你可以在此處 找到有關三種“大衛·辛克萊健康補品”的信息。 根據辛克萊的說法,這些補品會“啓動體內的長壽生物路徑”,或更確切地說,按照辛克萊的理解,可以保護定義細胞特異性的表觀基因組資訊免於受破壞。

許多研究,包括辛克萊團隊的,都顯示當人體處於卡咯里緊張狀態下(通過禁食自然達到這種狀態),體內的長壽生物路徑就會啓動。

互聯網有大量有關間歇性禁食的信息, 這裡這裡 有兩個簡單的初學者指南。

 


大衛·辛克 演講中的幾段節錄

2:22 - "Right now aging is not considered a medical condition ... Let's thing about it, why don't we?"

6:08 - We have a new understanding of what causes aging ... actually resetting the aging clock of the body.

8:33 - Aging is a loss of epigenetic information ... Information theory of Aging (ITA)

8:50 - Two types of information, genetic and epigenetic

10:10-38 - How epigenome looks and works

10:50 - It is epigenome that give cells their identity

11:09 - Epigenome is analogue information

11:50 One way of thinking of the epigenome is that it is the software of our cell, and the genome is the computer

12:54 - What happens is that cells lose their identities ... a nerve cell in an older person is no longer fully a nerve cell, ... and may be partly a skin cell.

13:28 - Question is though, can we slow this down? Can we reset the system? Is there a reboot? Is there a backup hard drive of this early set up, that we can access, and restore the early structure? ... I believe it is possible.

16:16 - Ten years of work ... is the discovery that broken chromosomes disrupt the structure of those hose reels (of epigenome), and cells start to lose their identities and don't function very well. And the ultimate outcome off cells losing their identities is aging. [3, 4]

17:36 - We can now measure age with great accuracy. ... This 100% quantitative. ... Measure

DNA “Methylome”. Measure which of the letter C’s, out of A, T, C, G, have a methyl group.

20:44 - Claude Shannon’s theory of information and “Schematic diagram of a correction system”.

21:38 - The transmitter in our fertilized egg, the receiver is our body in the future... We lose a lot of the information (in the course of our lives); we succumb to entropy.

22:04 - Man on the left (Yamanaka Shin'ji) won the Nobel Prize for learning how to make an adult cell into a stem cell. [1, 2]

22:32 - The four Yamanaka factors are called O, M, K, and M for short,

23:30 - "I think we finally found how to tap into the observer and reset our biological age, using the (three) Yamanaka factors (not including M)". [5]

23:48 - Give credit to a student in our lab, Wanqing Lu (first author of [5]).

24:38-57 - The "Optic Nerve Crush" experiment.

26:34 - "We can reprogram the retina of an old mouse and make it see just like a young mouse again".

27:08 - "We found the communicating device (the "backup hard drive of this early set up" mentioned at 13:28) back to the observer at least. There are a couple of enzymes, TED1 and TED2, that remove the chemical groups off the DNA group as part of that reset process".

28:40 - "NMN ... turns on the longevity pathway that we've worked on for many years".

30:05 - "What can you do if you don't want to go to the doctor and ask for metformin?" ...The best thing to do is to eat less often.... (and) Exercise ...

34:50 - 演講結束。答問時段開始

35:00 - Q: Why metformin, diabetes drug? A: Insulin is key.

37:26 - Q: What about the conventional hallmarks of aging. A: The proposed Information theory of aging (ITA) is upstream of the causes of those eight or nine hallmarks.

39:21 - Is oxidative damage (stress) upstream or downstream, or separate from ITA? Q: It is both. It's part of the positive feedback loop. Oxidative stress can cause DNA break. Also cosmic rays, CT scans, X-rays... A lot of vitamin C and mega doses of vitamin E can blunt the effects of a healthy diet and exercise.

41:40 - Q: What about non-nuclear oxidative damage; collagen or even extracellular things. A: Best way to tune on autophagy, chaperon mediated autophagy (to clean out damaging, unwanted proteins) is to fast for two days ...

 


參考文獻

[1] Takahashi, K.; Yamanaka, S. (2006). "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors". Cell. 126 (4): 663-676. https://doi.org/10.1016/j.cell.2006.07.024. PMID 16904174.

[2] Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. (2007). "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors". Cell. 131 (5): 861-872. https://doi.org/10.1016/j.cell.2007.11.019. PMID 18035408.

[3] Hayano et al. DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging. bioRxiv 2019Oct21, http://dx.doi.org/10.1101/808659

[4] Yang et al. Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals. bioRxiv 2019Oct19, http://dx.doi.org/10.1101/808642

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© HC Lee, February 2020, Taoyuan, Taiwan